Timeless Timolol?

Glaucoma's mainstay drug is nearing the big 4-0. Is age catching up with it?

By René Luthe, Senior Associate Editor

Imagine using a computer from the mid 1970s — or that “state of the art” item of stereo equipment, the 8-track tape player — to listen to your music. Funny, right? Both are enormous, by today's standards, operate slowly and don't perform as well as their modern counterparts. They're dinosaurs.

Yet glaucoma care providers are still relying heavily on a drug that was born when 8-track tape players were the epitome of cool: timolol. In medicine, a field in which revolutions occur regularly, timolol has yet to find itself on the ash-heap of history. Should it?

Nathan Radcliffe, MD, of Weill Cornell Medical College and New York Presbyterian Hospital, is one of the drug's many ardent defenders. He calls it one of the most trusted and versatile treatment options in glaucoma. Timolol therapy allows a 20% reduction in IOP with only once-daily dosing, he says — and an excellent topical tolerability profile. However, he also points out that recently the prostaglandin analog (PGA) class, which provides up to 30% IOP reduction with minimal systemic side effects, has become the primary treatment of choice for glaucoma.

He concedes other possible drawbacks to timolol as well: recent studies have called into question its 24-hour efficacy, and the effects of timolol on blood pressure and ocular perfusion pressure could be a potential limitation. The recent LOGTS study caused quite a bit of controversy in its finding that, despite similar IOP-lowering efficacy, brimonidine was associated with better visual field preservation than timolol in normal-tension glaucoma.¹ In this article, we will consider timolol's place in glaucoma management in 2012.

The PGA Question

A “younger” drug has, in a sense, surpassed timolol. Whereas it once held the title of number-one prescribed glaucoma medication, that title now belongs to the prostaglandins. Timolol has been relegated to the number two spot. Still, that's a far cry from saying that it will be consigned to a therapeutic time capsule anytime soon. Though PGAs can achieve greater IOP reduction (up to 10% higher) and have, unlike timolol, shown efficacy in reducing nocturnal IOP, not all eyes can tolerate them.

E. Randy Craven, MD, a glaucoma specialist from Denver, notes that some eyes cannot tolerate a prostaglandin. They tend to cause some hyperemia on the ocular surface, a particular problem for certain groups of patients, such as dark-complected African patients. “If there is even a little bit of redness in the whites of their eyes, it is very noticeable,” he says. These patients often prefer a beta-blocker. Patients with a history of CME, herpetic keratitis or uveitis also are better off with a beta blocker such as timolol, Dr. Craven says, which shows excellent tolerability.

“It's the single best locally tolerated eye drop for glaucoma,” says Dr. Radcliffe. “That's phenomenal.”

Not only is timolol better tolerated, it also helps patients better tolerate other glaucoma medications, Dr. Radcliffe explains.² “When you combine timolol with a prostaglandin analog, you can have a lower incidence of hyperemia than with a prostaglandin alone.” Thus timolol may be something the clinician would want to prescribe when both improved tolerability and IOP lowering are desired.

Given that approximately 40-60% of glaucoma patients are taking more than one medication, Gary Novack, PhD, president of PharmaLogic Development, points out, timolol's advantages in efficacy and ocular safety make it a valuable component of glaucoma therapy. “It's still an important part of therapy, it may just not be first-line therapy.”

Another advantage timolol may have over PGAs is that “it's probably that timolol is easier to put in a variety of different combinations than a PGA,” says Dr. Radcliffe.

And with cost-conscious healthcare insurers likely to continue pushing patients to generics, it is important to note that physicians have more confidence in generic versions of timolol than in the sole generic version of a PGA, which has been available a much shorter time.

Finally, timolol can match an important plus of the PGA class: it can be dosed once daily, always an advantage in a condition where patient compliance is such a problem.

The Night Shift

It's accepted that timolol won't lower intraocular pressure at night, but it appears that only PGAs will accomplish that anyway. That's because IOP is “maintained by aqueous humor production and drainage, and these factors change at night in such a way that some drugs can't alter these normal changes” according to Carol Toris, PhD, of the University of Nebraska Medical Center.

She has studied the efficacy of four drugs on nocturnal IOP: brimonidine, timolol, latanoprost and dorzolamide. Latanoprost was found to lower IOP at night when compared to no drug. The other three drugs did not change nocturnal IOP. The reason timolol and dorzolamide don't work at night, Dr. Toris ex plains, is that both are aqueous suppressants; aqueous flow normally decreases at night on its own, and the drug can't induce it to decrease further. “Something else is already working better,” she says.

Other studies, however, have shown that the topical CAIs can lower nocturnal IOP,³ notes Angelo Tanna, MD, director of the glaucoma service at Chicago's Northwestern University Feinberg School of Medicine.

Further, he observes that it still has not been proven that lowering IOP at night matters in glaucoma therapy. “At this time, we don't have evidence that supports the importance of lowering nocturnal IOP in patients with glaucoma. It is possible that other factors may mitigate the impact of the higher nocturnal IOP.”

Dr. Toris points out that the studies that have examined the value of IOP-lowering drugs, such as the Ocular Hypertension Treatment Study (OHTS), looked only at IOP measurements taken during the day. “But we don't know the therapeutic value of lowering IOP at night, because it's never been investigated.”

Come morning, however, timolol is effective at blunting the IOP rise that would occur then.

Pressure By Another Name

While nocturnal intraocular pressure may not be a serious consideration regarding the use of timolol, ocular perfusion pressure may be in some individuals. Dr. Tanna says it is that timolol does lower blood pressure and heart rate in some individuals. Therefore, it may lower ocular perfusion pressure at night. “That could potentially have a deleterious effect.” During the nocturnal period, he explains, timolol doesn't lower IOP, but it does lower blood pressure and heart rate, particularly in certain individuals; therefore, it may lower ocular perfusion pressure. Possibly patients who are predisposed to developing normal-tension glaucoma have a greater problem with blood pressure at night.

This graph from the LOGTS study shows little IOP reduction from baseline in either the timolol or brimonidine groups. Similar but very modest IOP lowering was achieved in each treatment arm. REPRINTED FROM THE AMERICAN JOURNAL OF OPHTHALMOLOGY, VOLUME 151, ISSUE 4, KRUPIN ET AL., A RANDOMIZED TRIAL OF BRIMONIDINE VERSUS TIMOLOL IN PRESERVING VISUAL FUNCTION: RESULTS FROM THE LOW-PRESSURE GLAUCOMA TREATMENT STUDY, PP. 671-681, COPYRIGHT 2011, WITH PERMISSION FROM ELSEVIER.

While the reduction in blood pressure that timolol brings about during the day is “more than offset,” Dr. Tanna says, by the reduction in IOP, at night, when timolol doesn't lower IOP, the drop in blood pressure could reduce ocular perfusion pressure. “It could render the optic nerve more susceptible to injury because of that,” Dr. Tanna says.

Thus, for normal-tension glaucoma patients, timolol is perhaps not a good choice of therapy, especially not for nighttime dosing. Dr. Tanna says he has long avoided its use in normal-tension glaucoma. “I think it's OK to use it once a day in the morning, but I would avoid using timolol at night in these patients.”

Dr. Tanna cites a study by Dr. Hayreh at the University of Iowa showing that among normal-tension glaucoma patients who had high blood pressure, for which they were being treated, use of timolol at night was an independent risk factor for progression in their visual fields.⁴ While the study was retrospective, Dr. Tanna notes that it is another piece of evidence indicating that for normal-tension glaucoma patients, timolol dosed at night may be deleterious.

Dr. Craven too only prescribes timolol in the morning, though he was led to this decision by Dr. Toris's work indicating that timolol did not lower IOP nocturnally.

The LOGTS Controversy

The recent Low-Pressure Glaucoma Treatment Study (LOGTS) report comparing timolol with brimonidine in preserving visual function has generated some scrutiny of timolol when it found that, although both drugs were efficacious in reducing IOP, brimonidine was associated with better visual field preservation in patients with normal-tension glaucoma. Many in the ophthalmic community, however, are skeptical of the finding, and are especially doubtful of the theory that timolol could have a neurodestructive effect.

Dr. Novack is among the skeptics. “To me, the study doesn't tell me about timolol; rather, it comes up with an interesting hypothesis about brimonidine.”

Harry Quigley, MD, director of the Dana Center for Preventive Ophthalmology at the Wilmer Eye Institute in Baltimore, also is leery of the findings regarding timolol. He notes that problems with the study's methodology and data analysis, plus a high drop out rate among the brimonidine group, indicate that the findings require repeating. Additionally, various editorials responding to the LOGTS report noted that, in their study, ocular pressure did not decrease to the percentage lowering that would have been considered the standard of care at the time the study was conducted.

Further, Dr. Quigley says, the rate at which the timolol group appears to have experienced visual field progression was “so spectacularly high that it was in itself remarkable.” Not even untreated glaucoma worsens as quickly as that, he says.

What about the long-term effect of timolol on glaucomatous visual field loss? Dr. Craven points out that there is much evidence, including Epstein's seminal study from 1989, indicating that timolol preserved vision, as opposed to not treating.⁵

Dr. Novack agrees. A four-year study that he coordinated looked at the long-term effects of timolol on IOP and visual fields.⁶ “We saw very little change in visual fields in those patients.”

In light of all this research, the LOGTS group's claim that timolol may be neurodestructive puts the investigators in a tricky position, Dr. Quigley feels. To accept their premise, “you are forced into a very strange conundrum — when timolol is used and it doesn't lower the eye pressure, that could be bad, but in the Ocular Hypertension Treatment study, it did lower the pressure, so then it was beneficial. Well, what ophthalmologist is using timolol when it doesn't lower the eye pressure? If it doesn't work, we stop it and we use something else.”

Its Place in Glaucoma Therapy Seems Secure

Timolol's long history of efficacy and tolerability mean that even with the advent of PGAs, it remains an essential tool in preserving vision. Dr. Quigley points out that timolol, as well as the whole beta-blocker class, has three major clinical studies that demonstrate the safety and efficacy of the class at different stages of glaucoma: OHTS, the Early Manifest Glaucoma Trial (EMGT) and the Collaborative Initial Glaucoma Treatment Study.

Dr. Tanna notes that the EMGT showed that the combination of betaxolol (a beta-blocker) and argon laser trabeculoplasty had no IOP-lowering effect in patients with normal-tension glaucoma with baseline IOPs of 15 mm Hg or lower.⁷ Therefore, it is not surprising that neither timolol nor brimonidine had much IOP-lowering efficacy in LOGTS. It is possible, he says, that the adverse impact on ocular perfusion pressure may not have been offset by sufficient IOP reduction in this patient population.

“When the pressure is lowered with a beta blocker, you get a protective effect,” Dr. Quigley says. “The jury is not out on that question.” OM

References

1. Krupin T, Liebmann JM, Greenfield DS, Ritch R, Gardiner S; Low-Pressure Glaucoma Study Group. A randomized trial of brimonidine versus timolol in preserving visual function: results from the Low-Pressure Glaucoma Treatment Study. Am J Ophthal. April 2011. 151(4):671-681.
2. Brandt JD, Cantor LB, MD, Katz LJ, Batoosingh AL, Chou C, Bossowska I; for the Ganfort Investigators Group II. Bimatoprost/Timolol Fixed Combination: A 3-month Double-masked, Randomized Parallel Comparison to Its Individual Components in Patients With Glaucoma or Ocular Hypertension. J Glaucoma. April/May 2008. 17(3): 211-6.
3. Liu JH, Medeiros FA, Slight JR, Weinreb RN. Comparing diurnal and nocturnal effects of brinzolamide and timolol on intraocular pressure in patients receiving latanoprost monotherapy. Ophthalmology. 2009 Mar;116(3):449-54. Epub 2009 Jan 20.
4. Hayreh SS, Podhajsky P, Zimmerman MB. Beta-blocker eyedrops and nocturnal arterial hypotension. Am J Ophthalmol. 1999 Sep;128(3):301-319.
5. Epstein DL, Krug JH, Hertzmark E, Remis LL, Edelstein DJ. A long-term clinical trial of timolol therapy versus no treatment in the management of glaucoma suspects. Ophthalmology. October 1989. 96:1460-167
6. Levobunolol Study Group. Levobunolol: A four-year study of efficacy and safety in glaucoma treatment. Ophthalmology. 1989;96:642-5.
7. Heijl A, Leske MC, Hyman L, Yang Z, Bengtsson B; EMGT Group. Intraocular pressure reduction with a fixed treatment protocol in the Early Manifest Glaucoma Trial. Acta Ophthalmol. 2011 Dec;89(8):749-54. doi: 10.1111/j.1755-3768.2009.01852.x. Epub 2010 Mar 17.