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Update on the Medical Treatment of Primary Open-Angle Glaucoma

Cheema, Anjum MD; Chang, Robert T. MD; Shrivastava, Anurag MD; Singh, Kuldev MD, MPH

The Asia-Pacific Journal of Ophthalmology: January/February 2016 - Volume 5 - Issue 1 - p 51–58
doi: 10.1097/APO.0000000000000181
Review Article

Glaucoma comprises a group of progressive, neurodegenerative disorders characterized by retinal ganglion cell death and nerve fiber layer atrophy. Several randomized controlled trials have consistently demonstrated the efficacy of intraocular pressure lowering to slow or halt the measurable progression of the disease. Medical therapy, in places where it is easily accessible, is often the primary method to lower intraocular pressure. We review the medical options currently available and possible future options currently in development. The 5 contemporary classes of topical agents in use include prostaglandin analogs, beta blockers, carbonic anhydrase inhibitors, alpha agonists, and cholinergics. In addition, several fixed combination agents are commercially available. Agents from each of these classes have unique mechanisms of action, adverse effects, and other characteristics that impact how they are used in clinical practice. Despite the plethora of medical options available, there are limitations to topical ophthalmic therapy such as the high rate of noncompliance and local and systemic adverse effects. Alternate and sustained drug delivery models, such as injectable agents and punctal plug delivery systems, may in the future alleviate some such concerns and lead to increased efficacy of treatment while minimizing adverse effects.

From the *Department of Ophthalmology, Kaiser Permanente, Atlanta, GA; †Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA; and ‡Department of Ophthalmology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY.

Received for publication October 7, 2015; accepted December 22, 2015.

Supported by a grant from Research to Prevent Blindness (to the Ophthalmology Department at the Albert Einstein College of Medicine/Montefiore Medical Center).

The authors have no conflicts of interest to declare.

Reprints: Anjum Cheema, MD, 1412 Bellsmith Dr, Roswell, GA 30076. E-mail:

The term glaucoma comprises a large number of primary and secondary causes of progressive retinal ganglion cell death and nerve fiber layer atrophy leading to increasing peripheral and central visual field loss over time and, in some cases, leading to blindness. The hallmark of glaucoma is the presence of cupping of the neuroretinal rim, particularly superiorly and inferiorly, and has among its risk factors advanced age, thin central corneal thickness, high intraocular pressure (IOP), and positive family history. There are other potential risk factors whose role is not yet clearly defined, among which notably are reduced ocular perfusion pressure and the possibility that lower intracranial pressure or increased translaminar cerebrospinal fluid (CSF) gradient differential may be associated with increased risk of glaucomatous progression. Among all glaucoma population-based studies around the world, the prevalence of glaucoma increases with age and with increasing IOP. In 2013, a meta-analysis of 50 population-based studies estimated the global prevalence of open-angle glaucoma (OAG) in people aged 40 to 80 years to be 3.54% (95% confidence interval, 2.09–5.82) or approximately 64.3 million, rising to an estimated 76 million by 2020.1 The total affected population is much larger when considering all types of glaucomas, including angle-closure, neovascular, uveitic, steroid-induced, postsurgical, etc. In fact, a Market Scope research report expects the global glaucoma pharmaceutical market to climb from roughly $4.7 billion in revenues in 2015 to nearly $6.1 billion in 2020 at a compounded annual rate of 5.1%.2 Ideally, glaucoma needs to be diagnosed as early as possible to preserve the most vision during a patient’s lifetime. At present, there is no way to functionally restore vision lost from glaucoma but regenerative therapy may be possible in the future. The goal of medical treatment for glaucoma is to lower an individual’s eye pressure to a level that preserves visual function to reduce morbidity such as diminished psychosocial functioning3 and falls,4 while maintaining a good quality of life. Because of the asymptomatic and insidious nature of most forms of glaucoma, particularly early in the disease process, screening eye examinations including IOP checks and examination of the optic nerve are commonly used to first make a diagnosis. Intraocular pressure is a well-established, modifiable risk factor for glaucomatous optic neuropathy, and medical therapy to reduce IOP has been proven to slow disease progression and reduce vision loss. However, occasionally, some patients still worsen despite maximal IOP lowering, underpinning the complex pathophysiology of accelerated ganglion cell loss in this multifactorial neurodegenerative disease process. This update on the medical treatment of primary OAG (POAG) will review the rationale for medical therapy, describe a practical clinical approach to deciding whether medical therapy should be initiated or changed, and provide an overview of current and new glaucoma agents on the horizon.

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As mentioned earlier, IOP lowering is the mainstay of treatment for glaucoma and medical, laser, and surgical methods of IOP lowering have all been shown in several randomized, controlled trials to reduce progression of vision loss. In a landmark study entitled “Latanoprost for open-angle glaucoma (UKGTS): a randomized, multicentre, placebo-controlled trial” in 2015, Garway-Heath et al5 published the first masked, randomized controlled trial (N = 516) providing evidence that latanoprost preserved visual function better than placebo for a 2-year period in patients with mild to moderate glaucoma. Given the ethical concern for the placebo arm subjects suffering vision loss during the trial, the authors designated the primary endpoint as a median visual field change of 1.6 dB in a single eye. All participants were monitored much more closely than routine clinical practice (16 fields in 24 months) and time to progression was confirmed by at least 4 visual fields. This reduced the chance that any progression in the control arm would meaningfully affect a participant’s visual quality of life. In fact, no measurable visual field deterioration was detected in two thirds of the placebo group after 2 years (mean IOP, 20.1 ± 4.8 mm Hg). The only other previously published glaucoma clinical trials with untreated control groups were a small study by Holmin et al6 and the multicenter Early Manifest Glaucoma Trial.7

The Early Manifest Glaucoma Trial was a US-Swedish collaborative study performed in the early 1990s, which concluded that lowering IOP effectively slowed visual field progression in early stage glaucoma. Before this study, the natural history of untreated early glaucoma was not well defined, and it was equally unclear whether early intervention made a difference in terms of visual preservation. From the 255 patients randomized to either laser trabeculoplasty and topical betaxolol hydrochloride or no treatment, the investigators found that an IOP reduction by a mean of 25% (5.1 mm Hg) reduced progression from 62% to 45% in the treated versus control groups, respectively, at 6-year follow-up. Criteria for visual field progression were computer based and defined as the same 3 or more test point locations, showing significant deterioration from baseline in glaucoma change probability maps from 3 consecutive tests. As soon as any progression was detected in the control group, these individuals were also offered treatment. On average, it took 4 years to detect early disease advancement.

Multiple other large glaucoma studies including the Advanced Glaucoma Intervention Study, which reported findings in 1998,8 the Collaborative Initial Glaucoma Treatment Study in 2001,9 and the Ocular Hypertension Treatment Study in 2002,10 all had treatment arms that demonstrated the benefit of lowering eye pressure at various stages of the disease. The primary aim of the Advanced Glaucoma Intervention Study was to determine whether laser trabeculoplasty or trabeculectomy would be preferred in patients with uncontrolled, advanced glaucoma. When IOP was stratified, it was shown that the group with lowest IOP had less overall change in visual field progression.8 Collaborative Initial Glaucoma Treatment Study sought to clarify whether surgical therapy or medical therapy was preferable in newly diagnosed glaucomatous patients. Patients were randomized to either medical therapy or trabeculectomy. Although greater IOP reduction was observed in the surgical arm at all time points, there was no difference in visual field progression. Notably, both arms had substantial IOP lowering (46% in the surgical arm, 38% in the medical arm).9 The Ocular Hypertension Treatment Study explored whether IOP lowering in ocular hypertensive patients decreased the likelihood of developing glaucoma. Patients were randomized to 20% IOP lowering or no treatment. The treatment arm had a 50% relative reduction in the incidence of conversion to glaucoma.10

Likewise, IOP lowering has been observed to be beneficial in eyes with normal- or low-tension glaucoma. The Collaborative Normal-Tension Glaucoma Study, published in 1998,11 established that among more than 140 patients with normal pressure and either documented progression, fixation-threatening field defects, or presence of disc hemorrhages, a 30% IOP reduction dropped the rate of disc or field progression from 35% in the observation group to 12% in the treated group, after correcting for the effect of cataract, which was greater in the treated group. More recently in 2011, the Low-Pressure Glaucoma Treatment Study, consisting of 178 patients randomized to 2 different treatment groups, determined that the use of brimonidine 0.2% was statistically less likely to be associated with progressive visual field loss than treatment with timolol 0.5%, even though there was no significant difference between the IOP-lowering effects of the 2 drugs in this multicenter, randomized controlled clinical trial.12 All of these major studies provided evidence in support of IOP reduction therapy in glaucoma. With the discovery of lower cerebral spinal pressure (CSF) by computed tomography cisternography in a small group of patients with normal-tension glaucoma13 and the retrospective finding of lower CSF pressure in POAG patients compared with that in nonglaucomatous controls,14 there is increasing evidence that translaminar (IOP-CSF) gradient pressures may explain why further IOP lowering helps even at “normal” pressures.

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Because there is no perfect biomarker for glaucoma or a single test that can confirm active disease, the decision to initiate or change therapy for glaucoma is usually based on the following factors: the life expectancy and quality of life of the patient, the IOP, the optic nerve appearance in combination with the retinal nerve fiber layer thickness, and visual field results. The current goal of glaucoma therapy is to lower IOP to a level that will preserve visual function for a patient’s lifetime.15 There is no way to accurately predict, prospectively, which level of IOP will guarantee that one will attain such a goal. This is because a safe IOP range for one patient’s optic nerves may not be generalizable to all patients. Reliable serial testing for glaucomatous progression via optic nerve visualization, optic nerve and retinal nerve fiber layer imaging [optical coherence tomography (OCT) or confocal scanning laser ophthalmoscopy], and visual field examination forms the cornerstone for personalized glaucoma management. Also, given the limited snapshots of suboptimal “true IOP” data, multiple preferred practice patterns have set forth guidelines for establishing a baseline IOP and estimated target pressure ranges on the basis of the severity of glaucoma.16,17 Staging of glaucoma patients is commonly divided into suspect, mild, moderate, and severe, on the basis of the estimated vertical cup-to-disc (C/D) ratio and visual field mean deviation (MD). Many research studies choose the same visual field mean deviation cutoffs with early MD better than −6 dB and not within 10 degrees of fixation, moderate MD −6 to −12 dB, and advanced MD worse than −12 dB or defect within 10 degrees of fixation. These definitions are loosely based on the Hodapp Parrish Anderson glaucoma grading scale criteria.18

The initial target pressure range is a suggested upper limit of IOP on the basis of longevity, quality of life, and risk factors for progression. This estimate is constantly adjusted during the course of follow-up, on the basis of disease stability or progression as determined by serial structure-function testing.19 However, what glaucoma specialists are really after is the estimated rate of glaucoma progression in a given eye, and multiple averaged pressure readings merely provide an estimate of the response to a given therapy. Thus, an alternate way of looking at target IOP is to follow a more dynamic treatment paradigm20 in which, instead of setting a periodically modified target IOP goal, a clinician makes an assessment on each patient visit regarding whether lowering a patient’s IOP with additional therapy is justified on the basis of the risk-benefit tradeoff at a given point in time based on a variety of patient-specific factors. With multiple OCT measurements of the retinal nerve fiber layer and visual field index information for individually calculated rates of progression, therapy can be personalized to each patient. Thus, requiring every mild, moderate, or severe glaucoma patient to have a specific target IOP range based on severity may be suboptimal in some circumstances. A cookbook approach to glaucoma patient care, particularly in terms of setting IOP goals, may lead, in some situations, to inappropriate care.

Medication choices in glaucoma care are affected by efficacy, safety, tolerability, compliance, persistence, and affordability—not necessarily in that order. Glaucoma therapy is usually chronic; and thus, it is important to check IOP multiple times to monitor a medicine’s therapeutic effect, while concomitantly providing serial testing for disease progression.21

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Currently, there are 5 classes of medications available to lower IOP. The efficacy, mechanism of action, and adverse effects of each class will be reviewed, followed by a short discussion on how to determine the optimal medicine depending on patient-specific and disease-specific variables.

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Prostaglandin Analogs

Prostaglandin analogs (PGAs) or hypotensive lipids, first introduced into the US market in 1996, have become the most common choice for initial therapy for glaucoma. Although the exact mechanism of action remains to be definitively elucidated, it is thought that these agents increase uveoscleral outflow by binding to receptors on the ciliary body, leading to upregulation of metalloproteinases and subsequent remodeling of the extracellular matrix to allow for increased aqueous humor outflow.22

There are 5 commercially available PGAs, including latanoprost, bimatoprost, travoprost, unoprostone, and tafluprost. Each is dosed nightly, with the exception of unoprostone, which is dosed twice daily. The most commonly used PGAs in clinical practice are latanoprost, bimatoprost, and travoprost. Each of these has been shown in prospective randomized controlled trials to be more efficacious as monotherapy compared with timolol, which was the most common first-line therapy before the introduction of PGAs. Latanoprost administered nightly produced a mean IOP reduction of 6.7 ± 3.4 mm Hg (27%) compared with 4.9 ± 2.9 mm Hg (20%) with twice daily timolol after 6 months of treatment.23 Similarly, in a meta-analysis of studies involving the use of latanoprost, monotherapy in patients with angle-closure glaucoma showed a 32.5% IOP reduction (−7.9 mm Hg).24 Travoprost 0.004% lowered IOP from a mean baseline of 26.8 mm Hg to 17.7 to 19.1 mm Hg (29%–34%) at 1 year, compared with a final IOP of 19.4 to 20.3 mm Hg from a similar baseline of 27.0 mm Hg (25%–28%) with timolol 0.5%.25 Similarly, bimatoprost produced a greater mean IOP reduction compared with timolol [8.1 (33%) vs 5.6 (23%) mm Hg, P < 0.001] after 6 months of treatment.26 Although some studies have suggested slightly greater IOP reduction with bimatoprost compared with latanoprost and travoprost,27 other studies have shown similar efficacy among all 3 agents.28

In contrast, tafluprost and unoprostone have less impressive results. Tafluprost, a preservative-free PGA, was shown to be noninferior to preservative-free timolol after a 12-week treatment period, reducing IOP from a baseline of 23.8–26.1 mm Hg to 17.4–18.6 mm Hg compared with a reduction from a baseline of 23.5–26.0 mm Hg to 17.9–18.5 mm Hg with preservative-free timolol.29 Unoprostone is associated with the least IOP lowering in this class of outflow drugs. This agent, although shown to produce clinically significant IOP reductions, was outperformed by timolol in a 6-month study, lowering IOP by 4.3 (17.8%) versus 5.8 (24.0%) mm Hg with timolol.30

In addition to their impressive efficacy, PGAs tend to be well tolerated with less than 5% of patients discontinuing treatment due to adverse effects.31 Although systemic adverse effects are rare, local adverse effects are fairly common, including conjunctival hyperemia, eyelash growth, and rarely, irreversible increased iris pigmentation.31 Prostaglandin-associated periorbitopathy, a condition characterized by periorbital fat loss, involution of dermatochalasis, and deepening of the upper eyelid sulcus, has increasingly been recognized as a common adverse effect of PGA therapy.32 Other possible but less definitive adverse effects include exacerbations of anterior uveitis, herpetic keratitis, and cystoid macular edema after cataract surgery.31

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Beta Blockers

Topical beta blockers (BBs) have been a mainstay of glaucoma treatment since their introduction in 1978. Their mechanism of action is reduced aqueous production via blockade of β-adrenoreceptors in the ciliary epithelium.33 These agents are most effective during waking hours but have little effect during sleep because of naturally reduced aqueous humor production at night.33 Another factor that sometimes limits their clinical use as long-term therapy is the relatively high rate of tachyphylaxis, approaching 50% at 2 years in 1 study.34

Nonselective β1 and β2 antagonists along with selective β1 antagonists are commercially available. Nonselective agents include timolol, levobunolol, metipranolol, and carteolol. Betaxolol is a selective β1 antagonist. Of these choices, timolol was the first introduced and remains the most commonly used agent. Timolol has been shown to reduce IOP by 20% to 35% on average and remains the US Food and Drug Administration’s “criterion standard” drug for glaucoma therapy against which new medications are commonly judged before approval.31 It is available in 0.25% and 0.5% concentrations used either once daily or twice daily and once daily gel-forming solutions. Levobunolol, available in 0.25% and 0.5% solutions typically administered twice daily, and metipranolol 0.3% administered twice daily have similar efficacy to timolol.35,36 Carteolol is unique in that its use is associated with intrinsic sympathomimetic activity producing an early, transient β-agonist response, which may partially protect against the systemic adverse effects of other β antagonists, including reduced pulse and blood pressure.31 Betaxolol is a cardioselective β1 antagonist, formulated to reduce the incidence of pulmonary β2-mediated adverse effects. This agent, however, is less effective in terms of IOP lowering, compared with other nonselective agents, with mean IOP reductions of 18% to 26%.31,37

Local adverse effects of BBs include conjunctival hyperemia, stinging, superficial punctate keratitis, and dry eye syndrome.31 They have also been shown to cause transient blurry vision by inducing higher order aberrations.38 Systemic adverse effects are an important consideration limiting the usefulness of these agents in certain patients, particularly those with severe heart disease, asthma, or chronic obstructive pulmonary disease. These possible effects include bradycardia, arrhythmia, cardiac conduction block, congestive heart failure, bronchospasm, masking of hypoglycemic symptoms in diabetics, depression, anxiety, impotence, and exacerbation or unmasking of myasthenia gravis.31

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Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors (CAIs) were first introduced in systemic form in 1954 and in topical form more recently in 1994. These agents selectively inhibit carbonic anhydrase isoenzyme II in the ciliary epithelium, leading to decreased aqueous production.31

Systemic CAIs include acetazolamide and methazolamide. Both are quite effective at lowering IOP, but adverse effects limit their utility for chronic IOP lowering. In clinical practice, they are often used as temporizing measures before surgery. Common adverse effects seen with systemic agents include paresthesias of the extremities, nausea, vomiting, and fatigue. More severe adverse effects include renal stones, electrolyte imbalances such as metabolic acidosis, hypokalemia, and hyponatremia. Rarely, the use of oral CAIs has been associated with bone marrow depression resulting in thrombocytopenia, agranulocytosis, and aplastic anemia. Carbonic anhydrase inhibitors should be avoided in patients with renal dysfunction and in patients with a sulfa allergy because CAIs are sulfonamides.

The first topical CAI to be introduced was dorzolamide in 1994, followed by brinzolamide in 1998. Dorzolamide is approved for thrice a day usage in the United States but is often used twice a day in other countries. Three times a day dosing has been found to result in IOP lowering of 18% to 22% and has been found to be equivalent to betaxolol but slightly inferior to timolol as monotherapy.39 Brinzolamide is available in suspension form with a physiologic pH of 7.4, causing it to be better tolerated than dorzolamide, which has a relatively acidic pH of 5.5.40 Brinzolamide has similar efficacy to dorzolamide.41

Topical CAIs have been found to be systemically safe, avoiding many of the significant systemic adverse effects of oral CAIs. Local adverse effects include bitter taste, stinging, burning, itching, and foreign body sensation. Brinzolamide in particular has been associated with transient blurry vision, attributed to increased light scattering.38 There have also been reports of irreversible corneal decompensation in patients with marked endothelial compromise, so topical CAIs should be used with caution or avoided in this patient group.31,42 Topical CAIs should be used with caution in patients with sulfa allergies. A recent retrospective study, interestingly, showed that patients with sulfa allergies had similar rates of adverse reactions to topical CAIs as patients with nonsulfa-related allergies, suggesting the possibility that patients with medication allergies of any kind may be more likely to develop allergies to other agents, without necessarily indicating that a self-reported sulfa allergy is a contraindication to topical CAI therapy.43

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Adrenergic Agonists

Adrenergic agonists (AAs) are available in both nonselective forms, which target both α- and β-adrenergic receptors, and selective forms, which target only α-adrenergic receptors.

Nonselective agents, including epinephrine and its prodrug dipivefrin, work primarily by increasing aqueous outflow through the trabecular meshwork (TM) and the uveoscleral pathway. These agents have been associated with 15% to 25% IOP reductions, but their use has declined greatly in modern clinical practice.44 Systemic adverse effects include headache, palpitations, high blood pressure, and anxiety, whereas local effects include pupillary dilation, conjunctival hyperemia, and conjunctival adrenochrome deposits with long-term administration.31

Selective α-AAs include apraclonidine and brimonidine and decrease IOP by both enhancing outflow and decreasing aqueous production.31 Apraclonidine has been shown to produce 20% to 27% mean IOP reductions but has been associated with a high rate of allergic blepharoconjunctivitis and is typically used for short-term prophylaxis against IOP spikes after anterior segment laser surgery.45,46 Brimonidine, available as 0.2%, 0.15%, and 0.1%, is a highly selective α2 agonist. It is approved for use thrice daily in the United States but is often used twice daily in some regions of the world. Brimonidine 0.2% has been shown to be equivalent to timolol at reducing IOP at peak (2 hours after morning dose; 5.9–7.6 vs 6.0–6.6 mm Hg IOP reduction for brimonidine and timolol, respectively) but less effective at trough levels (12 hours after evening dose; 3.7–5.0 vs 5.9–6.6 mm Hg IOP reduction, respectively).47 In another study, brimonidine was shown to reduce IOP by approximately 24% from a baseline of 23.6 mm Hg.48 In addition to its IOP-lowering effect, there has been great interest regarding the potentially neuroprotective effects of brimonidine. In an animal model of rats with laser-induced ocular hypertension, it was shown to reduce the rate of retinal ganglion cell loss from 33% to 15%.49 Moreover, in a randomized controlled trial of low-tension glaucoma patients treated with either brimonidine or timolol, the eyes treated with brimonidine had slower rates of visual field progression despite similar IOP lowering in each group. Subsequent analysis showed that this protective effect of brimonidine was independent of mean ocular perfusion pressure or IOP-related effects, suggesting a possible neuroprotective mechanism.50 Systemic adverse effects reported with brimonidine include dry mouth, fatigue, and headache, whereas local adverse effects include allergic blepharoconjunctivitis occurring in 12% to 15% of patients after several months of therapy. An important and serious systemic adverse effect is central nervous system and respiratory depression in small children due to the ease with which these agents cross the blood-brain barrier, making its use absolutely contraindicated in children younger than 2 years old and relatively contraindicated in those younger than 6 years.31 Brimonidine 0.15% and 0.1% have been formulated with a stabilized oxychloro complex in place of benzalkonium chloride (BAK) producing lower yet still significant rates of allergy (9.2% vs 15.7%, P = 0.007).48

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Cholinergic, or parasympathomimetic agents, were the first medications introduced for the treatment of glaucoma over 100 years ago.31 They are available as direct agonists of parasympathetic receptors in the eye or as indirect agonists, which inhibit aceteylcholinesterase. Cholinergic agents work by increasing aqueous outflow through the TM.

Pilocarpine is a direct agonist and is available in various concentrations from 0.5% to 8%. It is applied 4 times daily because of its short duration of action, and it has been shown to reduce IOP by 20% to 30%.31 However, it has some notable adverse effects, including diminished visual acuity due to pupillary constriction and accommodative spasm, brow ache, and rarely retinal detachment. Systemic adverse effects are uncommon but may include increased salivation, diarrhea, sweating, vomiting, and tachycardia. Echothiophate iodide is an indirect agent used twice daily with comparable IOP reduction to pilocarpine. It has similar adverse effects as pilocarpine but is also associated with a cataractogenic effect and with prolonged respiratory paralysis during general anesthesia if suxamethonium chloride is used as a muscle relaxant.31 In general, cholinergic agents are used much less frequently because newer agents with improved dosing and side effect profiles have been developed, but they are still an important part of the medical armamentarium for glaucoma in select patients, particularly in those who are pseudophakic or aphakic.

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Fixed Combinations

Often, multiple medications are necessary for adequate IOP lowering, and there are several fixed combination therapies available worldwide. In the United States, the currently available options are Cosopt (dorzolamide 2%-timolol 0.5%), Combigan (brimonidine 0.2%-timolol 0.5%), and Simbrinza (brinzolamide 1%-brimonidine 0.2%).

Dorzolamide-timolol dosed twice daily has been shown to be equivalent to instillation of dorzolamide thrice daily and timolol twice daily [IOP reductions of 5.1 mm Hg (20.5%) and 4.9 mm Hg (20.0%) with combination and its components administered separately, respectively].51 Similarly, brimonidine-timolol was found to be equally efficacious to concomitant administration of its components, brimonidine and timolol, producing an IOP reduction of 4.4 to 5.3 mm Hg for a 12-week period, with a similar safety profile.52 In a separate randomized trial, brimonidine-timolol was associated with a 32.3% (−7.7 mm Hg) IOP reduction from an untreated baseline.53 The most recently approved fixed combination in the United States, brinzolamide-brimonidine administered thrice daily, has been shown to be superior to monotherapy with either of its components for a period of 6 months (26.7%–36% with combination vs 22.4%–27.9% with brinzolamide and 20.6%–31.3% with brimonidine).54 Similarly, a randomized trial showed brinzolamide-brimonidine fixed combination to be noninferior to concurrent application of both brimonidine and brinzolamide [−8.5  (32.2%) mm Hg for fixed combination vs −8.3  (31.3%) mm Hg for concurrent brimonidine and brinzolamide].54

Fixed combination agents offer several advantages of concomitant administration of their components, including increased patient adherence and persistence with therapy, decreased potential for washout of first medication by instillation of second, decreased exposure to preservatives and possibly improved tolerability, and potentially decreased costs.55

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Which Agent to Choose?

Prostaglandin analogs are the most commonly used topical agents for initial medical treatment of glaucoma and ocular hypertension due to excellent efficacy and relatively favorable side effect profiles, particularly with regard to systemic adverse effects, relative to several other classes of drugs. However, despite the excellent efficacy of PGAs, a large percentage of patients will require additional therapy to meet IOP reduction goals. Thirty-nine percent of eyes in the Ocular Hypertension Treatment Study required 2 or more medications to reach a 20% IOP reduction, and at least 50% of patients in the Collaborative Initial Glaucoma Treatment Study required 2 or more medications to reach treatment goals.9,56 If PGA use does not allow adequate IOP reduction, the most common agents to consider next would be BBs, CAIs, or AAs. The most important factors to consider when beginning adjunctive therapy are efficacy, ease of administration, side effect profile, and tolerability. It is important to note that the efficacy of each of these agents when used in conjunction with a PGA is significantly different than when each is used as monotherapy. A systematic review and meta-analysis of the adjunctive effect of BBs, CAIs, or AAs with concomitant use of PGAs reported a statistically similar mean diurnal IOP-lowering efficacy (2.3–3.0 mm Hg) among all agents, whereas CAIs and BBs were more efficacious at intermediate (4–9 hours after administration) and trough (9–12 hours after administration) levels compared with AAs.57 In patients with ocular allergy and intolerance to multiple medications, consideration should be given to either preservative-free formulations or BAK-free formulations. Timolol, dorzolamide-timolol, and tafluprost are available without preservatives, whereas travoprost and brimonidine are available in formulations preserved with an alternative to BAK. Finally, as mentioned previously, fixed combinations offer several advantages such as ease of administration and increased compliance. However, the law of diminishing returns applies as third and fourth IOP-lowering medications are added, as 1 study has shown only 14% of patients achieving an additional 20% IOP reduction with the addition of third or fourth adjunctive IOP-lowering agents.58 In such patients, surgery or laser trabeculoplasty should be considered.

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There are several novel medications currently under investigation, which may potentially increase the armamentarium of glaucoma therapies in the future. Additionally, in response to the many limitations associated with traditional topical ophthalmic agents, there has been a rapid expansion and development of technologies to circumvent common limitations, such as poor compliance, adnexal adverse effects, and difficulties in the self-administration of eye drops. It is hoped that novel drug delivery devices currently in trials will alleviate many of these concerns. Indeed, sustained release (SR) systems represent one of the most exciting aspects of research to improve glaucoma care.59

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Novel Medications

Rho Kinase Inhibitors

Rho kinase inhibitors, also known as ROCK inhibitors, may be the next potential class of glaucoma medications. Agents are being tested in late phase multinational trials alone and in combination with existing classes of medications such as BBs and PGAs. ROCK inhibitors are thought to work by multiple mechanisms, and the most common adverse effect is hyperemia. The IOP-lowering effects are achieved primarily by increasing trabecular outflow and improving optic nerve perfusion via complex interactions with the contractile properties of outflow tissues and possibly by decreasing episcleral venous pressure.60,61 There are several ROCK inhibitors that have undergone extensive study, with Rhopressa (Aerie Pharmaceuticals) currently in phase 3 trials, which initially failed to meet the primary endpoint in Rocket 1, but met a modified primary endpoint in Rocket 2, and with Rockets 3 and 4 in the pipeline.62 Other ROCK inhibitors have been abandoned in the past because of both efficacy and tolerability issues. Given the multiple potential benefits of ROCK inhibitors, there has been considerable interest in this class of medications. It has been postulated that these agents have potential neuroprotective benefits as well, which will require further study.

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Trabodenoson (Selective α-1 Adenosine Mimetic)

Trabodenoson (Inotek Pharmaceuticals, Lexington, Mass) has recently completed promising phase 2 trials, reporting not only impressive IOP lowering, but also excellent tolerability.63 The medication is thought to improve trabecular outflow by enhancing and upregulating protease activity (protease A and MMP-2), thereby augmenting the normal physiology of the TM. Of significance as well is the potential for a neuroprotective effect of trabodenoson on retinal ganglion cells, a function that has remained largely elusive in the current armamentarium of glaucoma therapies.

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Sustained Drug Delivery


Compliance with commonly prescribed eye drop regimens has been repeatedly demonstrated to be suboptimal across a multitude of studies. Poor compliance to medical regimens accounts for substantial worsening of disease and increased healthcare costs, irrespective of how compliance is measured. To further add to the problem, studies have concluded that physicians are poor at predicting the degree of patient compliance and patients consistently overrepresent their degree of adherence.10,64–67 A large retrospective review of more than 18,000 glaucoma patients in California demonstrated that less than one third of glaucoma patients were considered “highly compliant” and found that adherence during the first 2 years of treatment was the best predictor of future adherence.65

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Punctal Plug Delivery Systems

The concept of punctal occlusion to improve local absorption of topical medications has been examined for decades with variable and contradictory results.68,69 The demonstration of successful SR using these devices, however, is a relatively recent development. A review of preferences of currently available SR systems in Singapore revealed that patients significantly preferred punctal plug delivery systems over subconjunctival and intracameral routes, although all 3 were preferred over topical administration by subsets of the population.70

Early phase trials have been conducted by QLT, Mati Therapeutics, and Ocular Therapeutix on SR punctal plug delivery systems of prostaglandin analogs. These studies have demonstrated promising initial results, with the reported sustained IOP lowering of punctal plug delivered travoprost similar to topical timolol at time points during the course of 2 to 3 months. Low rates of adverse events have been reported to date, and the technology demonstrates significant promise by mitigating the major limitations of eye drop therapy with a simple delivery system. Many of the current iterations of this delivery system are made with absorbable polymers, obviating the need for removal of a previously inserted device. Larger trials in the future will help further understand potential limitations and benefits of these delivery systems.

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Given major paradigm shifts in intravitreal therapeutics for macular degeneration, diabetes, and other retinal vasculitides, the concept of repeated injections of medications has become more accepted by patients and providers alike. The primary sites for injectable SR delivery systems include the subconjunctival space, the anterior chamber, and the vitreous body. Each offers unique advantages and disadvantages, and trials continue to help elucidate the differences between the various methods.

In animal models, polyesteramide microfibers have successfully delivered latanoprost in both canine and rabbit models.71 pSivida (Watertown, Mass), in a modification of the already existing Durasert implantable bioerodable, is examining subconjunctival and intracameral insertion of latanoprost depot injections in early trials. Envisia (Morrisville, NC) and Ohr Pharmaceucticals (New York City, NY) are both in the preclinical trial phase with injectable nanoparticle technologies to administer travoprost and latanoprost, respectively. Nanotechnology offers tremendous promise in drug delivery because of distinct advantages over standard emulsions in terms of the amount and consistency of the deliverable medication.

Compared with punctal plug and other extraocular drug delivery methods, direct administration of medication into the anterior or posterior chamber has the advantage of not relying on corneal penetration. Perhaps the greatest advantage of intracameral delivery of medications is the potential for major reductions in adnexal adverse effects. The major disadvantages include the increased risk of toxicity, the potential for physical compromise of delicate intraocular structures, and the necessity of lifelong procedures to maintain sustained IOP lowering. At the time of this publication, SR bimatoprost injections are in phase 3 clinical trials (Allergan, Irvine, Calif).

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The art of glaucoma therapy is founded upon an understanding of not only the therapeutic potency of a particular agent, but also an appreciation of its practical limitations. Our ability to determine and quantify disease progression has vastly improved with advancements in structural imaging and functional paradigms. Several large randomized clinical trials have validated the important benefits of IOP lowering in slowing disease progression. Although highly effective when used correctly, topical therapies have major limitations in clinical practice. Because interventional procedures continue to advance, it is likely that medical and surgical therapy of glaucoma will continue to overlap, and safe and effective drug delivery systems may challenge the existing paradigm of eye drop therapy. Novel classes of medications may become available to replace and augment our current therapeutics by allowing for better IOP control and, perhaps in the future, directly preserving optic nerve health.

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Throughout the centuries there were men who took first steps, down new roads, armed with nothing but their own vision.

— Ayn Rand




glaucoma; topical therapy; adverse effects; sustained drug delivery; rho kinase

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