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The Effect of Latanoprost vs Timolol on Intraocular Pressure in Patients with Glaucoma and Ocular Hypertension

Mario V Aquino, MD, Margarita Lat-Luna, MD
Glaucoma Unit, Department of Ophthalmology, University of the Philippines College of Medicine,
Manila, The Philippines.

The objective of this study was to compare the effect on intraocular pressure (IOP) of latanoprost 0.005% once daily with timolol 0.5% twice daily in patients with open angle glaucoma or ocular hypertension. The study was designed as a single-centre, randomised, double-masked parallel-group comparison of latanoprost with timolol after 12 weeks of treatment.

60 patients with open angle glaucoma or ocular hypertension with IOP of at least 22 mm Hg were included. Administration of previous ocular hypotensive medication necessitated a wash-out period of 5 to 21 days before the start of the study treatment. The patients were randomised to treatment with latanoprost 0.005% once daily or timolol 0.5% twice daily. Mean diurnal IOP was measured at baseline and after 6 and 12 weeks of treatment.

After 6 weeks of treatment, the diurnal IOP reduction (mean ± standard error of the mean [SEM]) in the latanoprost group was 12.1 ± 1.1 mm Hg (41%; p < 0.001; analysis of covariance [ANCOVA]) and 8.7 ± 1.1 mm Hg (30%; p < 0.001; ANCOVA) in the timolol group. The difference of 3.4 ± 1.6 mm Hg was statistically significant in favour of latanoprost (p = 0.034; ANCOVA). A 30% reduction or more in mean diurnal IOP was achieved by 71% of patients in the latanoprost group and by 34% of patients in the timolol group. After 12 weeks of treatment, the diurnal IOP reduction (mean ± SEM) in the latanoprost group was 11.1 ± 1.2 mm Hg (39%; p < 0.001; ANCOVA) and 9.1 ± 1.1 mm Hg (32%; p < 0.001; ANCOVA) in the timolol group.

Most side effects observed were mild and transient and no serious adverse events were reported. Latanoprost 0.005% administered once daily in the evening was at least as effective as timolol 0.5% twice daily in reducing the mean diurnal IOP after 6 and 12 weeks of treatment. Both medications were well tolerated during the study period.

Asian J Ophthalmol 1999;1(3):3-7.
Key Words: Glaucoma; Ocular hypertension; Diurnal intraocular pressure; Latanoprost; Timolol.

Latanoprost (13,14-dihydro-17- phenyl-18,19,20-trinor-    prostaglandin    F2    -   isopropylester, previously PhXA41) has proven to be an effective ocular hypotensive drug.1-7 The mechan-ism of action is an increase in aqueous humour outflow, with little or no effect on aqueous humour production.8,9 Lata-noprost administered to monkey eyes increased uveoscleral outflow with no effect on conventional outflow,10 and a corresponding effect has indirectly been demonstrated in humans.8 In long-term studies, latanoprost 0.005% applied once daily reduced intraocular pressure (IOP) at least as effectively as ß-adrenergic antagonists.2-5 After 1 to 2 years of treatment, the IOP reduction is maintained with no evidence of major drift of IOP over time.6,7 Latanoprost is well tolerated both locally and sys-temically. Apart from mild conjunctival hyperaemia and some other transient ocular symptoms, the only adverse re-action of clinical importance noted in long-term studies was increased pigmen-tation of the iris,2-4,6,7 most probably due to increased melanin production in the melanocytes. The purpose of this study was to compare the effect of latanoprost administered once daily with timolol administered twice daily for 12 weeks in patients with open angle glaucoma or ocular hypertension in a Philippine population. In addition, ocular and systemic safety variables were monitored and reported throughout the study.

Patients and Methods

The study was a single-centre, random-ised, double-masked parallel-group comparison of latanoprost 0.005% administered once daily with timolol 0.5% administered twice daily. After obtaining approval from the Medicine Control Council and the Ethics Committee of the University of the Philippines, a signed informed consent was obtained from all patients before enrolment in the study. The study followed the guidelines of the Declaration of Helsinki.

Patients with unilateral or bilateral open angle glaucoma, capsular glaucoma, pigmentary glaucoma, or ocular hypertension were included in the study. If both eyes fulfilled the eligibility criteria they were both regarded as study eyes and the mean IOP was used for the analysis. Inclusion criteria also comprised a minimum age of 18 years, no prior glaucoma treatment or only single-drug treatment for elevated IOP and IOP of at least 22 mm Hg at the prestudy visit with or without medication. If the patients were receiving single-drug glaucoma treatment, they were eligible after a wash-out period of at least 21 days for ß-adrenergic antagonists, 14 days for adrenergic agonists and 5 days for cholinergic agonists and carbonic anhydrase inhibitors. Exclusion criteria included use of any medications other than glaucoma drugs, closed or barely open anterior chamber angle, ocular surgery or argon laser trabeculoplasty within the last 3 months, current use of contact lenses, ocular inflammation within the last 3 months, any condition preventing reliable appla-nation tonometry, current pregnancy or lactation, pregnancy consideration, or inability to adhere to the protocol design. After inclusion in the study, the pa-tients were randomly assigned to either latanoprost treatment, in which placebo eye drops were given in the morning and latanoprost 0.005% eye drops in the evening, or timolol treatment, in which timolol 0.5% eye drops were given twice daily (figure 1). 


Figure 1. Study outline.
Figure 1

At the pre-study visit, both medical and ocular histories were taken. Gonio-scopy and perimetry were carried out unless recently performed. Also, visual acuity and refraction, slit-lamp examina-tion, ophthalmoscopy, and IOP measure-ment were performed. This pre-study visit took place 1 month before the study started and the patients were included after these eligibility assess-ments. If the patients were taking a single-drug glaucoma treatment, an appropriate wash-out period was allowed for before the start of the study, as out-lined above. During the study period of 12 weeks there were 4 scheduled follow-up visits: at baseline and after 2, 6, and 12 weeks.

Table 1. Diastolic perfusion pressure versus glaucoma risk.
Characteristics 

Latanoprost(n=30)

Timolol (n=30) 


Sex (male/female)
mean age(range)
Asian race
Eye colour   homogenously brown
Primary open angle   glaucoma
Exfoliation glaucoma
Ocular hypertension

17/13
58 (21-92)
30
30

26

1
3

21/9 
56 (20-86) 
30 
30 

29 



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Results

The IOP was measured with a calibrated Goldmann applanation tono-meter. Three measurements were per-formed in each eye. The mean of the 3 measurements was used in the statistical analyses. The IOP was measured at 9.00 am, 1.00 pm and 5.00 pm at the baseline visit, and at weeks 6 and 12, whereas IOP was measured only at 9.00 am at the week 2 visit. Best corrected Snellen visual acuity and refractive error were determined at each visit and a slit-lamp examination was performed. Flare was graded as none, mild, mode-rate, or severe and cells present in a slit width of 2 mm were graded as none (1 cell), mild (3-5 cells), moderate (6-20 cells) or severe (>20 cells). At the prestudy visit and at the week 12 visit ophthalmoscopy was performed through dilated pupils. Iris and en face photo-graphs were taken at the baseline visit and at the week 12 visit.

An analysis of covariance (ANCOVA) was performed with diurnal IOP change as a response variable, baseline diurnal IOP as a covariate and the group as a study effect. The difference between the latanoprost group and the timolol group was estimated from the ANCOVA. The mean diurnal IOP was defined as the mean of the measurements at 9.00 am, 1.00 pm and 5.00 pm.

60 patients were included in the study with 30 patients randomised to each of the latanoprost and timolol groups, res-pectively. The patients' characteristics are presented in table 1. There was no significant difference between the 2 treatment groups with respect to age, sex distribution, or diagnosis. Of the 60 patients included, 53 completed the study. Of the 7 patients withdrawn, 4 participated in the week 6 visit and the IOP measurements from this visit could be incorporated in the week 6 analysis. Patients were withdrawn for the following reasons: lost to follow-up (3 patients), systemic hypertension (2 patients) and increased IOP (2 patients).

After 6 weeks of treatment, latano-prost reduced the diurnal IOP from 29.9 ± 1.8 mm Hg (mean ± SEM) to 17.3 ± 1.2 mm Hg. Timolol treatment reduced the diurnal IOP from 28.7 ± 1.5 mm Hg (mean ± SEM) to 20.5 ± 1.2 mm Hg. The diurnal IOP reduction in the latanoprost group was 12.1 ± 1.1 mm Hg (41%; p < 0.001; ANCOVA) and 8.7 ± 1.1 mm Hg (30%; p < 0.001; ANCOVA) in the timolol group from the overall baseline of 29.3 mm Hg. The difference of 3.4 ± 1.6 mm Hg was statistically significant in favour of latano-prost (p = 0.034; ANCOVA) [figure 2]. A 30% reduction or more in mean diurnal IOP at week 6 compared with baseline was achieved by 71% of the patients in the latanoprost group and by 34% of the patients in the timolol group.

Figure 2. Change in diurnal intraocular pressure (IOP) [mean±SEM] from baseline to week 5.
Figure 2

After 12 weeks of treatment, the diurnal IOP was reduced to 17.7 ± 1.3 mm Hg (mean ± SEM) in the latanoprost group and to 19.4 ± 1.2 mm Hg (mean ± SEM) in the timolol group. The diurnal IOP reduction in the latanoprost group was 11.1 ± 1.2 mm Hg (39%; p < 0.001; ANCOVA) and 9.1 ± 1.1 mm Hg (32%; p < 0.001; ANCOVA) in the timolol group. The difference of 2.1 ± 1.6 mm Hg in diurnal IOP reduction between the 2 groups from the overall baseline of 28.7 mm Hg, was in favour of latanoprost but not statistically significant (p = 0.21; ANCOVA). The mean diurnal IOP at each measurement for the two treatment groups is shown in figure 3.

Figure 3. Diurnal intraocular pressure (IOP) [mean±SEM] at baseline, week 6 and week 12 for the latanoprost and timolol groups. At week 2, IOP was measured in the morning.
Figure 3

Table 2 shows the percentage of patients reaching a specific target IOP of between 15 mm Hg and 20 mm Hg at the week 6 visit. A mean diurnal IOP of ± 15 mm Hg was reached by 46% of the patients in the latanoprost group compared with 10% of timolol patients.

Ocular and systemic adverse events reported during the study are presented in table 3. In this table, the withdrawn patients are included. However, for the patients remaining in the study most events were reported as mild. No cells or flare in the anterior chamber were reported for any patient during the study. Iris photograph and slit-lamp examinations did not reveal any changes in the pigmentation of the iris. No serious adverse events were reported.

Table 2. Percentage (%) of patients who reached a specific target intraocular pressure (IOP) at week 6.
Diurnal IOP 

Latanoprost (n=28)

Timolol (n=29) 


15 mm Hg
16 mm Hg
17 mm Hg
18 mm Hg
19 mm Hg
20 mm Hg

46
46
54
54
71
79

10 
21 
41 
45 
45 
48 

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