Medical therapy for glaucoma: Advances and needs

Glaucoma is a chronic disease, and its management stretches through years of a patient’s lifetime. Currently, medical treatment is a significant element of managing patients with glaucoma.

Although many advances have been made in medical therapy for glaucoma in recent decades, no ideal glaucoma medication yet exists.

Producing this ideal medication is the challenge faced by those who are involved in the research and production of medical therapies.

Preserving structure and function

The goal of therapy for patients with glaucoma is to preserve visual function. Physicians have many ways of measuring the preservation of optic nerve structure and function: by judging the thickness of the nerve fiber layer, the size of the central cup or the inclination of the walls, or by assessing patients’ visual function with perimetry or visual acuity testing. But physicians do little to measure the quality of their patients’ lives.

Some global instruments are used for determining patients’ overall health-related quality of life. One of them, a survey called the short-form 36,¹ was used in the Ocular Hypertension Treatment Study,² but, because it is not a vision-specific quality-of-life indicator, it provided little information for ophthalmologists. Cataracts dramatically diminish a patient’s quality of life, and an instrument with 14 questions called the VF-14 has been used to show the benefit of cataract surgery in patients with visual disability.³ Vision-specific quality of life has also been evaluated in glaucoma patients.⁴

In addition to preservation of visual function in glaucoma patients, ophthalmologists are also concerned about preservation of structure and function of the optic nerve and the nerve fiber layer. Modalities for imaging the structure of the optic nerve include optic disc drawing, optic disc stereo photography and optic disc topography. Modalities for evaluating the nerve fiber layer include red-free photographs, scanning laser polarimetry, scanning laser ophthalmoscopy and optical coherence tomography. To think that any one of these technologies by itself will be best either for determining the presence of glaucoma or for judging its rate of progression across the spectrum of the disease is naive. A multimodal approach to diagnosis and monitoring of disease progression is needed.

To document the preservation of visual function, perimetry offers many options. Standard automated perimetry (SAP) has been an advance over Goldmann perimetry, in which the physician controlled the test stimulus. Since the introduction of automated perimetry in the 1980s, computer algorithms have further increased the efficiency of automated testing. Frequency doubling technology has found its place in screening for glaucoma. Short wavelength automated perimetry (SWAP) has been noted to detect glaucomatous damage earlier that standard white-on-white perimetry. However, these technologies are less accepted by physicians across the spectrum of the disease than standard white-on-white perimetry, as typified by the Humphrey 24-2 test with Swedish interactive threshold algorithm (SITA) standard testing.

The goal of therapy

Although the goal [of glaucoma therapy] is to preserve visual function, the ultimate goal is to maintain or improve the patient’s quality of life. — Richard Parrish II, MD

Once a physician determines that a patient has glaucoma or has experienced progression of the disease, what is the goal of therapy? Although the goal is to preserve visual function, the ultimate goal is to maintain or improve the patient’s quality of life. Vision-related quality of life cannot be determined easily, and, subsequently, ophthalmologists depend upon a surrogate, which is maintenance of IOP at a target level. Medical therapy, laser therapy and surgical therapy are three options for managing IOP.

Neuroprotection, the unstated goal of all treatments for glaucoma, is the desired end point. At present, neuroprotection is associated only with the lowering of IOP. Researchers understand and hope that a way of preserving structure and function that is independent of IOP will be found. At least one drug, memantine, is being evaluated in phase 3 clinical studies for this application. The results of those studies have not yet been published.

The “perfect” drug

Efficacy

What is the ideal glaucoma drug? This question can be addressed from a number of standpoints: The physician is most concerned with efficacy and safety, and the patient or user of the drug is concerned with its convenience.

From an efficacy standpoint, the ideal drug would provide demonstrable preservation of visual function and structure associated with its IOP-lowering effect over a prolonged period.

The perfect glaucoma drug would lower IOP to a target range of 10 mm Hg to 12 mm Hg, the range of episcleral venous pressure. The drug would provide constant IOP lowering, without peaks and troughs. Diurnal fluctuations of IOP over the course of a 24-hour period have been demonstrated,⁵ as well as differences in IOP when the subject is sitting vs. in the supine position.⁶ With the ideal drug, IOP would remain constant throughout sleep and the activities of daily living and would not be affected by postural changes.

According to data from the Advanced Glaucoma Intervention Study (AGIS), patients who have lower IOPs have less likelihood of progression of glaucomatous damage. Despite some shortcomings in that study, it is generally accepted that most glaucoma patients are better served by pressures that are lower rather than higher. Data published in a later report by the AGIS group⁸ indicate that patients whose pressures fluctuate over a long period tend to have greater visual field loss.

Safety

The perfect drug is, above all else, safe. A drug that is efficacious in lowering IOP but is not safe is of no value. It must be safe for the eye and safe systemically as well.

An ideal drug would not alter systemic blood pressure and would not affect cardiac, hepatic, neurologic or renal health. In the eye, a drug should not cause ocular surface changes, follicular conjunctivitis, hyperemia or toxicity to proliferating cells — the cells of the conjunctiva or corneal epithelium.

Convenience

From a patient’s perspective, the perfect drug has other aspects that a physician may not consider. For patients, the best medical therapy is easy to use. A longer lasting treatment effect is desirable. A once-weekly drug would be better than a once-daily drug, and monthly or yearly dosing would be even better.

An ideal treatment would also be inexpensive; however, with the cost of drug development currently at about $1 billion per new drug, that may not be possible. Application can be topical, but perhaps subconjunctival or intravitreal administration may be feasible if the safety profile justifies that approach.

Ultimately, the patient would like to have a “pacemaker maintenance” mentality toward this ideal medication, so that daily attention would not be necessary.

Limitations of current therapies

In reality, the ideal drug does not exist. The limitations of current medical therapy options include relatively frequent application — in the best case, one drop daily. Patients must remember to use their medications and remember how to use them.

Current medical therapy is better than it was in the past, but it is still lacking several key attributes to ensure effectiveness and patient adherence. — Richard Parrish II, MD

A patient’s persistence and adherence to a medical regimen are important, but these are not dependent simply on the safety or efficacy of the drug. Adherence depends on the patient’s ability to acquire the medication. Barriers to acquisition can include cost or the absence of the drug from a payer’s formulary. Adherence depends on the patient’s ability to maintain an adequate supply of the medication, to correctly instill the topical drop and to remember to use the medication regularly.

Alternatives to medical therapy

Alternatives to medical therapy exist. In a way, laser therapy of the open angle, such as argon laser trabeculoplasty (ALT) or selective laser trabeculoplasty (SLT), is similar to adding another drop to a patient’s therapeutic regimen; it lowers IOP effectively for a period, but cannot be considered curative.

In the Glaucoma Laser Trial,⁹ ALT was at least as effective and safe at 2 years’ follow-up as timolol medical therapy when used as first-line therapy (Figure 1). Data show, however, that the treatment effect of ALT declines over time (Figure 2).¹⁰ The short-term success rate of ALT is 65% to 95%, with a reduction in IOP of 20% to 30%. But in the long-term, the attrition rate is 5% to 10% per year, leaving the 5-year success rate of ALT at 50%.¹⁰

SLT poses an alternative to ALT, although no long-term prospective comparative studies exist. In a retrospective comparative study by Juzych and colleagues,¹¹ however, with follow-up of 5 years or more, outcomes with the two techniques were similar.

Conclusion

Current medical therapy is better than it was in the past, but it is still lacking several key attributes to ensure effectiveness and patient adherence. The next generation of drugs must lower IOP more efficiently, be easier to use, require less frequent application and, ultimately, demand less of the patient, both psychologically and financially.

Efficacy of ALT vs. medical therapy as first-line treatment Figure 1. As first-line therapy, ALT is nearly as effective in reducing IOP as a therapeutic regimen. Data adapted from The Glaucoma Laser Trial Research Group. Ophthalmology. 1990;97:1403-1413.

Treatment effect of ALT over time Figure 2. Data show the treatment effect of ALT declines over time. Data adapted from Shingleton BJ, Richter CU, Dharma SK, et al. Ophthalmology. 1993;100:1324-1329.

References

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2. Gordon MO, Kass MA. The Ocular Hypertension Treatment Study: Design and baseline description of the participants. Arch Ophthalmol. 1999;117:573-583.
3. Steinberg EP, Tielsch JM, Schein OD, et al. The VF-14. An index of functional impairment in patients with cataract. Arch Ophthalmol. 1994;112:630-638.
4. Parrish RK 2nd. Visual impairment, visual functioning, and quality of life assessments in patients with glaucoma. Trans Am Ophthalmol Soc. 1996;94:919-1028.
5. Drance SM. The significance of the diurnal tension variations in normal and glaucomatous eyes. Arch Ophthalmol. 1960;64:494-501.
6. Mosaed S, Liu JH, Weinreb RN. Correlation between office and peak nocturnal intraocular pressures in healthy subjects and glaucoma patients. Am J Ophthalmol. 2005;139:320-324.
7. The Advanced Glaucoma Intervention Study Group. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130:429-440.
8. Nouri-Mahdavi K, Hoffman D, Coleman AL, et al. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology. 2004;111:1627-1635.
9. The Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT). 2. Results of argon laser trabeculoplasty versus topical medicines. Ophthalmology. 1990;97:1403-1413.
10. Shingleton BJ, Richter CU, Dharma SK, et al. Long-term efficacy of argon laser trabeculoplasty. A 10-year follow-up study. Ophthalmology. 1993;100:1324-1329.
11. Juzych MS, Chopra V, Banitt MR, et al. Comparison of long-term outcomes of selective laser trabeculoplasty versus argon laser trabeculoplasty in open-angle glaucoma. Ophthalmology. 2004;111:1853-1859.