Systemic Hemodynamics and Ocular Perfusion in Normal-Tension Glaucoma: Evaluation of Beta-Blocker Effect

Abstract

Purpose:

To compare the effects of topical treatments with and without beta-blockers on diurnal and nocturnal intraocular pressure (IOP), systemic blood pressure (BP), and ocular perfusion pressure (OPP) in patients with normal-tension glaucoma (NTG).

Methods:

NTG patients followed at the Glaucoma Unit of the Department of Ophthalmology, Sakarya University Training and Research Hospital between 2020 and 2025 were retrospectively analyzed. Patients receiving beta-blocker-containing therapy (Group 2, n = 21) and nonbeta-blocker therapy (Group 1, n = 18) were included. Twenty-four-hour IOP and systolic/diastolic BP (DBP) measurements were recorded, and OPP was calculated. Optical coherence tomography parameters and visual field tests were also evaluated.

Results:

Patients using beta-blockers had significantly lower diurnal and nocturnal systolic BP (SBP) compared to the nonbeta-blocker group (P₁= 0.012, P₂= 0.048). No significant differences were observed in DBP between groups during diurnal and nocturnal periods (P₁= 0.126, P₂= 0.255). There were no significant differences between groups in 24-h mean IOP values or IOP fluctuation (P₁= 0.590, P₂= 0.753). Diurnal OPP was significantly lower in the beta-blocker group, while nocturnal OPP did not differ between groups (P₁= 0.012, P₂= 0.258). Ganglion cell–inner plexiform layer thickness was higher in the nonbeta-blocker group (P = 0.012). No significant differences were observed in other structural or functional measurements (retinal nerve fiber layer, P = 0.599; mean deviation, P = 0.457; pattern standard deviation, P = 0.805).

Conclusions:

In NTG patients, beta-blocker use reduces diurnal SBP and diurnal OPP but has no significant effect on 24-h IOP or nocturnal OPP. These findings support the critical role of systemic hemodynamics and ocular perfusion in NTG progression and suggest that beta-blockers should be monitored carefully for OPP effects, especially in normotensive patients.

INTRODUCTION

Normal-tension glaucoma (NTG) is a subtype of primary open-angle glaucoma associated with glaucomatous optic disc changes and visual field defects in the absence of elevated intraocular pressure (IOP).1 Although IOP is within normal limits in NTG, disease progression cannot be explained solely by mechanical factors, suggesting that vascular mechanisms play a significant role in its pathogenesis.2

Reduction in ocular blood flow (OBF) is a key component in NTG pathogenesis and is particularly associated with decreased ocular perfusion pressure (OPP).3 OPP is determined by the difference between systemic blood pressure (BP) and IOP. In NTG, where IOP is within the normal range, systemic BP plays a major role in OPP regulation.4 Several studies have reported that nighttime BP dips can reduce OPP, impair optic nerve perfusion, and constitute an important risk factor for NTG progression.5,6

Vascular dysregulation and impaired autoregulation can lead to fluctuations in OBF, contributing to optic nerve ischemia.7 A subset of NTG patients exhibits primary vascular dysregulation or Flammer syndrome, which is associated with perfusion instability along with features such as cold extremities, migraine, and vasospastic tendencies.1

Topical beta-blockers, commonly used in glaucoma treatment, can enter systemic circulation and reduce nighttime BP, potentially further lowering OPP in NTG patients. However, data on the effects of beta-blockers on diurnal and nocturnal hemodynamic parameters in NTG are limited and inconclusive.

The aim of this study was to compare the effects of beta-blocker-containing and nonbeta-blocker treatments on diurnal and nocturnal IOP, BP, and OPP in NTG patients, with a particular focus on whether nocturnal OPP reduction is more pronounced in patients using beta-blockers.

METHODS

Patients diagnosed with NTG and followed at the Glaucoma Unit of the Ophthalmology Clinic, Sakarya University Training and Research Hospital, between 2020 and 2025 were included in the study.

Inclusion criteria were IOP below 21 mmHg, stable use of topical treatment for at least three months, and availability of 24-hour IOP, systolic BP (SBP), and diastolic BP (DBP) recordings. Patients with secondary glaucoma, pseudoexfoliation or pigment dispersion syndrome, recent ocular surgery, and cardiovascular disease were excluded from the study. For hypertensive patients, systemic medications were reviewed, and those using systemic beta-blockers were excluded to avoid potential confounding effects on BP and ocular perfusion measurements.

Patients were divided into two groups according to their topical antiglaucomatous treatment: beta-blocker-containing treatment (timolol 0.5%) and nonbeta-blocker treatment. For all patients, IOP and systemic BP measurements recorded at 09:00, 11:00, 13:00, 15:00, 17:00, 19:00, 22:00, 24:00, 04:00, and 07:00 were reviewed. IOP was measured using Goldmann applanation tonometry by the same trained investigator, and BP was measured manually by sphygmomanometry. Measurements between 09:00 and 19:00 were considered the diurnal period, while measurements at 22:00, 24:00, 04:00, and 07:00 were considered the nocturnal period; mean values were calculated for each period.

In addition to IOP measurements, diurnal (09:00–19:00) and nocturnal (22:00, 24:00, 04:00, and 07:00) systemic BP measurements were analyzed, and mean values were calculated for each period. Mean OPP was calculated by first calculating mean arterial pressure (MAP) using the standard formula: MAP = DBP + ⅓ (SBP– DBP). Then, mean OPP was obtained using the formula: OPP = ⅔ MAP– IOP.

Additional variables recorded included age, sex, central corneal thickness (CCT), number of topical medications, retinal nerve fiber layer (RNFL), and ganglion cell–inner plexiform layer (GC-IPL) thickness measured by optical coherence tomography (OCT), and visual field test (VFT) parameters including mean deviation (MD) and pattern standard deviation (PSD). Diurnal and nocturnal IOP, SBP, DBP, and OPP parameters were compared between the groups.

Statistical analyses

Statistical analyses were performed using the SPSS software version 21.0 for Windows (SPSS Inc., Chicago, IL, USA). Due to the small sample size, nonparametric tests were used. The continuous variables were compared between the groups using the Mann–Whitney U-test. The categorical variables were compared using the Chi-square test, when sample sizes were small or cell counts insufficient, Fisher’s exact test was applied. The relationship between OPP parameters and beta-blocker use was evaluated using multivariable linear regression analysis, controlling for potential confounders including age, sex, number of topical medications, and corneal thickness. P < 0.05 was considered statistically significant in all analyses.

RESULTS

A total of 39 patients were included: 18 patients receiving nonbeta-blocker antiglucomatous therapy (Group 1) and 21 patients receiving beta-blocker-containing therapy (Group 2). The mean age was 63.72 ± 16.57 years in Group 1 and 59.95 ± 8.01 years in Group 2 (P = 0.061). In Group 1, 4 patients (22.2%) had diabetes mellitus (DM) and 10 patients (55.6%) had hypertension (HT), while in Group 2, DM and HT rates were 38.1% (n = 8) and 57.1% (n = 12), respectively. No statistically significant differences were observed between the groups in terms of DM and HT distribution (P₁ = 0.380; P₂ = 0.829, respectively). The mean follow-up duration was 3.58 ± 4.01 years in Group 1 and 5.60 ± 4.40 years in Group 2, with no significant difference between the groups (P = 0.233) [Table 1].

Table 1.

Demographic characteristics of patients

	Group 1 (non β-blocker)	Group 2 (β-blocker)	P
Number of patients	18	21	-
Age (years)	63.72±16.57	59.95±8.01	0.061
Diabetes mellitus, n (%)	4 (22.2)	8 (38.1)	0.380
Hypertension, n (%)	10 (55.6)	12 (57.1)	0.829
Follow-up duration (years)	3.58±4.01	5.60±4.40	0.233

Regarding the topical antiglucomatous medications used, 10 patients (25.6%) received prostaglandin alone, 5 patients (12.8%) brimonidine alone, 3 patients (7.7%) prostaglandin + brimonidine, 10 patients (25.6%) a combination of carbonic anhydrase inhibitor + beta-blocker + brimonidine + prostaglandin, 5 patients (12.8%) prostaglandin + carbonic anhydrase inhibitor + beta-blocker, and 6 patients (15.4%) prostaglandin + beta-blocker + brimonidine. Patients using beta-blockers were all included in Group 2 regardless of additional medications. Accordingly, beta-blockers were used only as adjunctive therapy in this cohort and not as first-line monotherapy.

The mean number of topical medications was 1.33 ± 0.48 in Group 1 and 3.21 ± 0.90 in Group 2 (P < 0.001). Mean CCT was 540.77 ± 47.81 μm in Group 1 and 531.34 ± 30.65 μm in Group 2, with no significant difference (P = 0.528) [Table 2].

Table 2.

Structural and functional ocular parameters

	Group 1 (non β-blocker)	Group 2 (β-blocker)	P
CCT, µm	540.77±47.81	531.34±30.65	0.528
Average C/D ratio	0.75±0.08	0.76±0.07	0.722
Vertical C/D ratio	0.74±0.09	0.75±0.07	0.782
RNFL thickness (µm)	67.28±14.86	63.87±11.98	0.599
GC-IPL thickness (µm)	73.29±10.08	63.99±11.12	0.012*
MD, dB	–7.70±6.50	–10.45±8.90	0.457
PSD, dB	7.26±4.47	6.58±4.22	0.805
BCVA (logMAR)	0.06±0.07	0.07±0.06	0.605

*P<0.05. CCT: Central corneal thickness, C/D: Cup-to-disc ratio, RNFL: Retinal nerve fiber layer, GC-IPL: Ganglion cell-inner plexiform layer, MD: Mean deviation, PSD: Pattern standard deviation, BCVA: Best-corrected visual acuity

The mean cup-to-disc (C/D) ratio was 0.75 ± 0.08 in Group 1 and 0.76 ± 0.07 in Group 2 (P = 0.722), whereas the vertical C/D ratio was 0.74 ± 0.09 and 0.75 ± 0.07, respectively (P = 0.782). The mean RNFL thickness was 67.28 ± 14.86 μm in Group 1 and 63.87 ± 11.98 μm in Group 2 (P = 0.599). Mean GC-IPL thickness was significantly higher in Group 1 (73.29 ± 10.08 μm) than in Group 2 (63.99 ± 11.12 μm, P = 0.012). VFT parameters, including MD and PSD, were not significantly different between the groups (MD: −7.70 ± 6.50 vs. −10.45 ± 8.90, P = 0.457; PSD: 7.26 ± 4.47 vs. 6.58 ± 4.22, P = 0.805) [Table 2].

Best-corrected visual acuity (logMAR) was 0.06 ± 0.07 in Group 1 and 0.07 ± 0.06 in Group 2 (P = 0.605) [Table 2]. Mean IOP under topical treatment was 12.36 ± 1.87 mmHg in Group 1 and 12.48 ± 1.93 mmHg in Group 2, with no significant differences (P = 0.590). Twenty-four-hour IOP measurements ranged from 9.88 ± 1.32 to 14.94 ± 2.28 mmHg in Group 1 and from 10.21 ± 2.04 to 14.95 ± 2.09 mmHg in Group 2, with no significant differences in minimum or maximum IOP values (P₁ = 0.809; P₂ = 0.649). IOP fluctuation was 5.05 ± 1.76 mmHg in Group 1 and 4.73 ± 1.38 mmHg in Group 2 (P = 0.753). Mean diurnal IOP was 12.27 ± 1.85 mmHg in Group 1 and 12.69 ± 1.92 mmHg in Group 2, whereas mean nocturnal IOP was 12.48 ± 2.51 mmHg and 12.30 ± 2.41 mmHg, respectively, with no significant differences (P₁ = 0.236; P₂ = 0.752) [Table 3].

Table 3.

Intraocular pressure parameters

	Group 1 (non β-blocker)	Group 2 (β-blocker)	P
Mean IOP (mmHg)	12.36±1.87	12.48±1.93	0.590
24-h minimum IOP (mmHg)	9.88±1.32	10.21±2.04	0.809
24-h maximum IOP (mmHg)	14.94±2.28	14.95±2.09	0.649
IOP fluctuation (mmHg)	5.05±1.76	4.73±1.38	0.753
Diurnal IOP (mmHg)	12.27±1.85	12.69±1.92	0.236
Nocturnal IOP (mmHg)	12.48±2.51	12.30±2.30	0.752

IOP: Intraocular pressure

Twenty-four-hour BP measurements showed that in Group 1, mean diurnal SBP was 133.33 ± 15.16 mmHg, and DBP was 75.27 ± 4.95 mmHg, whereas mean nocturnal SBP was 124.72 ± 14.26 mmHg, and DBP was 72.77 ± 9.73 mmHg. In Group 2, mean diurnal SBP was 121.59 ± 12.52 mmHg, and DBP was 73.26 ± 7.02 mmHg, whereas mean nocturnal SBP was 116.30 ± 10.99 mmHg and DBP was 69.34 ± 5.05 mmHg. Diurnal and nocturnal SBP values were significantly lower in the beta-blocker group (P₁ = 0.012; P₂ = 0.048), whereas DBP values were similar between groups (P₁ = 0.126; P₂ = 0.255) [Table 4].

Table 4.

Systemic blood pressure and ocular perfusion pressure

	Group 1 (non β-blocker)	Group 2 (β-blocker)	P
Diurnal SBP (mmHg)	133.33±15.16	121.59±12.52	0.012*
Nocturnal SBP (mmHg)	124.72±14.26	116.30±10.99	0.048*
Diurnal-nocturnal SBP difference (mmHg)	8.61±5.7	5.28±2.31	0.097
Diurnal DBP (mmHg)	75.27±4.95	73.26±7.02	0.126
Nocturnal DBP (mmHg)	72.77±9.73	69.34±5.05	0.255
Diurnal-nocturnal DBP difference (mmHg)	2.50±2.12	3.91±2.45	0.654
Diurnal MAP (mmHg)	94.62±7.98	89.37±8.75	0.008*
Nocturnal MAP (mmHg)	90.09±10.91	85.00±6.68	0.134
Mean MAP (mmHg)	49.51±5.37	45.92±5.87	0.031*
Diurnal-nocturnal MBP difference (mmHg)	4.53±2.20	4.37±3.88	0.415
Diurnal OPP (mmHg)	50.80±5.15	46.88±6.46	0.012*
Nocturnal OPP (mmHg)	47.57±7.31	44.49±5.21	0.258

*P<0.05. SBP: Systolic blood pressure, DBP: Diastolic blood pressure, MAP: Mean arterial pressure, MBP: Mean blood pressure, OPP: Ocular perfusion pressure

Mean diurnal MAP was 94.62 ± 7.98 mmHg in Group 1 and 89.37 ± 8.75 mmHg in Group 2 (P₁ = 0.008), whereas mean nocturnal MAP was 90.09 ± 10.91 mmHg and 85.00 ± 6.68 mmHg, respectively (P₂ = 0.134). The diurnal–nocturnal MAP difference was 4.53 ± 2.20 mmHg in Group 1 and 4.37 ± 3.88 mmHg in Group 2, with no significant difference (P = 0.415) [Table 4].

Mean diurnal OPP was significantly lower in Group 2 (46.88 ± 6.46 mmHg) compared to Group 1 (50.80 ± 5.15 mmHg, P = 0.012), whereas nocturnal OPP did not differ significantly between groups (Group 1: 47.57 ± 7.31 mmHg; Group 2: 44.49 ± 5.21 mmHg, P = 0.258) [Table 4]. The diurnal and nocturnal hourly intergroup changes in MAP and OPP are illustrated in Figures 1 and 2, respectively.

Figure 1.

Diurnal and nocturnal hourly ıntergroup changes in mean arterial pressure. MAP: Mean arterial pressure

Figure 2.

Diurnal and nocturnal hourly ıntergroup changes in ocular perfusion pressure. OPP: Ocular perfusion pressure

DISCUSSION

In this study, the effects of beta-blocker-containing and nonbeta-blocker antiglucomatous treatments on 24-h IOP, systemic BP, and OPP were compared in patients with NTG. Diurnal and nocturnal SBP were significantly lower in patients using beta-blockers, whereas no significant differences were observed between the groups in diastolic BP during diurnal and nocturnal. Diurnal OPP was significantly lower in the beta-blocker group, whereas nocturnal OPP did not differ significantly between the groups. In contrast, 24-h IOP values and IOP fluctuations were comparable between patients using beta-blockers and those not receiving beta-blockers.

Despite normal IOP in NTG, the development of glaucomatous optic neuropathy suggests that vascular mechanisms play a critical role in disease pathogenesis.7 Low OPP has been reported to reduce optic nerve head perfusion, contributing to disease progression.8 Therefore, not only IOP but also hemodynamic parameters such as systemic BP and OPP are crucial in the course of NTG.

The use of topical beta-blockers in NTG remains controversial due to their potential effects on optic nerve head blood flow. It should be emphasized that in this study, beta-blockers were not prescribed as first-line therapy but were added as adjunctive treatment in patients with insufficient IOP control or disease progression despite other topical medications. These agents have vasoconstrictive properties and have been shown in previous studies to enhance physiological nocturnal systolic and diastolic hypotension, reduce heart rate, and decrease arterial oxygen saturation.5,6,9,10,11 These effects raise concerns about potential negative impacts on OPP in NTG patients. Indeed, in our study, diurnal OPP was significantly lower in patients using beta-blockers. Although nocturnal OPP did not show a significant difference, the reduction in nocturnal SBP may potentially compromise optic nerve perfusion reserve over time, posing a risk for disease progression. However, some studies in the literature have not confirmed this relationship, indicating heterogeneous results.

Among topical beta-blockers, timolol maleate is the most commonly used agent. Since the late 1970s, timolol has been extensively evaluated for its efficacy and safety in glaucoma treatment.12 Although generally well tolerated topically, systemic absorption can cause contraindications in conditions such as sinus bradycardia, chronic obstructive pulmonary disease, heart block, and heart failure. Topical beta-blockers have also been shown to reduce BP and heart rate in glaucoma patients.13

Comparative clinical studies evaluating topical beta-blocker use in NTG have reported that nonselective beta-blockers like timolol achieve greater IOP reduction, whereas β1-selective agents such as betaxolol are associated with better preservation of visual fields.14 This suggests that the systemic BP-lowering effects of nonselective beta-blockers may negatively affect visual function, especially in NTG patients.15 In our study, all patients using beta-blockers received timolol, suggesting that the observed hemodynamic findings may be related to this agent.

Previous studies have reported that 8-week treatment with 0.5% timolol twice daily significantly reduced SBP throughout the day and DBP during daytime in patients with glaucoma or ocular HT. Mean 24-h systolic OPP was also significantly reduced compared to baseline, and timolol was reported to decrease nocturnal heart rate.16 In contrast, a meta-analysis reported that topical timolol caused small decrease in systolic and diastolic BP without significant effects on OPP.17

In our study, no significant differences in 24-h IOP or IOP fluctuations were observed between beta-blocker users and nonusers, consistent with previous studies reporting limited IOP-lowering contributions of beta-blockers in NTG.11,12

Regarding OCT parameters and visual field indices, no significant differences were found between groups, except for GC-IPL thickness, which was higher in the beta-blocker-free group. The factors such as a higher number of medications used, more advanced disease, or treatment-resistant cases in the beta-blocker group may have contributed to the reduced GC-IPL thickness, representing potential confounders. Therefore, while our findings suggest a possible effect of beta-blockers on neuronal loss, prospective and longitudinal studies are needed to clarify this relationship.

The literature indicates that over-dipping of nocturnal BP is associated with more severe visual field loss in glaucoma patients with normal diurnal BP, whereas patients with diurnal HT experience milder visual field loss even with over-dipping (MD: −16.6 dB vs. −3.9 dB; P = 0.004).18 In our study, the lower diurnal systolic and mean arterial BP in beta-blocker users supports the critical role of systemic perfusion in NTG pathophysiology. Low diurnal BP may reduce optic nerve perfusion reserve and increase susceptibility to physiological nocturnal BP reductions. Therefore, the observed diurnal BP reduction in our study could be considered a potential risk factor for progressive optic nerve damage by decreasing OPP in NTG patients.

This study has several limitations. First, as a retrospective design, measurements were not standardized under investigator control, which may have affected 24-h IOP and BP readings. Second, the relatively small sample size limits statistical power. Third, the simultaneous use of multiple antiglucomatous medications in the beta-blocker group complicates attributing observed differences in OPP and structural measures solely to beta-blockers. Fourth, the study includes only single-time-point 24-h monitoring, which may not reflect long-term hemodynamic fluctuations reported in the literature. Measurement times may also have affected patients’ natural sleep patterns. Finally, long-term structural and functional progression was not assessed, preventing causal inference regarding the clinical effects of beta-blockers.

In conclusion, in NTG, beta-blocker use should be carefully evaluated due to its effects on systemic BP and OPP rather than IOP control alone. In patients with low diurnal systemic BP, potential reductions in OPP may pose a risk for disease progression. Confirmation of these findings and a better understanding of the long-term clinical effects of beta-blockers require prospective, longitudinal studies with larger sample sizes.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.