IOP Matters

Abstract

To date, evidence from multiple randomized controlled trials has shown that effective intraocular pressure (IOP) lowering therapy significantly reduces the risk of glaucomatous progression across all stages of the disease. Changes in IOP have a substantial impact on the load-bearing connective tissues of the optic nerve head (ONH), as well as the overlying neurovascular tissues of the ONH and retina. An initial treatment goal of reducing IOP by 25% to 35%—and possibly more in advanced cases—can help prevent progression. Additionally, maintaining stable IOP by minimizing both diurnal and long-term fluctuations may further enhance disease control and reduce the risk of worsening.

Precis

As supported by multiple randomized controlled trials, lowering intraocular pressure effectively slows glaucomatous progression.

When the obvious is unclear

In 1987, the glaucoma community was taken by surprise when Eddy and Billings questioned the value of lowering intraocular pressure (IOP) lowering for treating glaucoma.¹ They argued that there is little evidence supporting the effectiveness of ocular hypotensive treatment for glaucoma. Moreover, they suggested that its use might be driven more by a perceived obligation of clinicians to take action than by demonstrated clinical benefit. They argued that we needed to know whether or not treatment yielded a better outcome than the natural history of glaucoma. Some ophthalmologists viewed the Eddy and Billings analysis as an assault on the dogma that IOP-lowering did make a difference for glaucoma patients. Others saw it as a challenge to apply evidence-based medicine to glaucoma treatment. In retrospect, it may have been an inflection point that stimulated the development and application of impactful clinical trials to glaucoma diagnosis and management.

To date, evidence from multiple randomized controlled trials has demonstrated that appropriate IOP lowering therapy is highly effective in preventing or slowing further glaucomatous progression at all stages of the disease. Aiming for a 25% to 35% reduction in IOP, and perhaps even more for patients with more advanced glaucoma can be an initial target to prevent glaucoma progression. In addition, optimizing control of both diurnal and long-term IOP fluctuations may contribute to improved disease stability and reduced progression risk.

Normal tension glaucoma (NTG)

Ironically, the first impactful trial that showed that lOP lowering therapy was effective in preventing the progression of open angle glaucoma evaluated patients with ‘normal’ pressures. The Collaborative Normal-Tension Glaucoma Study (CNTGS) was initiated at a time when it still was unclear whether NTG was an IOP-related optic neuropathy.² One eye of study subjects was randomized to treatment or observation, with all eyes receiving treatment if progression was observed or fixation was threatened. To be eligible for randomization, the NTG eyes had to show documented progression of field defects or a new disc hemorrhage or had to have field defects that threatened fixation when first presented for the study. The treated group achieved a 30% reduction in IOP using medications, laser and surgery. It had a mean 12% risk of visual field (VF) progression, whereas the untreated group had a 35% risk of progression over the follow up period.³ The study concluded that IOP lowering was effective in slowing glaucoma progression even when the IOP range was within ‘normal’ range.

Newly diagnosed glaucoma or early glaucoma

Early Manifest Glaucoma Trial (EMGT)

Perhaps more than any other study until recently, the EMGT addressed the questions posed by Eddy and Billings. This controlled clinical trial randomized patients with early open-angle glaucoma (OAG) to either IOP lowering therapy or observation. Once randomized, the treated patients received betaxolol and argon laser trabeculoplasty, and Xalatan was added if IOP exceeded 25 mmHg on more than one occasion.⁴ After a mean follow-up period of 6 years, progression was noted in 62% of patients in the observation group and in 45% of patients in the treatment group. Although the IOP reduction in treated EMGT patients was relatively modest (mean 25% reduction), the study demonstrated that IOP lowering therapy reduced the risk of progression by 50% and that every mmHg IOP lowering resulted in a 10% reduction in such risk.⁵

Collaborative Initial Glaucoma Treatment Study (CIGTS)

Although the primary objective of the CIGTS was to determine whether initial surgical therapy is preferable to initial medical therapy in patients with newly diagnosed glaucoma, it also confirmed that IOP reduction prevents glaucoma progression.⁶ The study was valuable as a target IOP, determined by baseline VF severity, was assigned to each patient. In addition, quality of life also was assessed. Overall vision-related quality of life was similar between the medication and surgery groups. The rate of progression of OAG was lower in CIGTS than in many other clinical trials, possibly because of more aggressive IOP-lowering goals (38%−46%) applied during the earlier stages of the disease. The subsequent report, demonstrated that a lower mean IOP, a lower minimum IOP, and lower sustained levels of IOP over follow-up were significantly predictive of less VF loss. Interestingly, around 15 % of eyes had substantial VF improvement (VF greater than 3 dB gain) after 5 years which was associated with better IOP control.⁷

Advanced glaucoma

Advanced Glaucoma Intervention Study (AGIS)

AGIS mainly was designed to evaluate treatment algorithms (argon laser trabeculoplasty–trabeculectomy–trabeculectomy (ATT) vs. trabeculectomy–argon laser trabeculoplasty–trabeculectomy (TAT)) and also to provide treatment recommendations for eyes with advanced glaucoma.⁸ However, perhaps the most impactful parts were analyses assessing the relationship between IOP and VF progression. The goal of treatment for all patients was to lower IOP below 18 mmHg at all time points. It was observed that the subgroup of patients in both treatment arms who had IOPs lower than 18 mmHg at every visit throughout the study had no VF progression. These patients had a mean IOP of 12.3 mmHg⁹

Ocular hypertensives

In contrast to OAG, the needs for medication in patients with ocular hypertension were less certain. However, with the completion of the Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS), the natural history of untreated vs. treated ocular hypertension is now well established.^{10, 11} In OHTS,¹⁰ participants from 23 participating sites in the United States were included with an IOP between 24 mm Hg and 32 mm Hg. The goal in the medication group was to reduce the IOP by 20% or more and to reach an IOP of 24 mm Hg or less. At five years, the study showed efficacy of treatment for prevention of glaucoma; approximately 4.4% of treated patients developed OAG vs. approximately 9.5% of untreated patients, approximately 50% relative risk.

In EPGS,¹¹ the subsequent European counterpart to the OHTS, the effect of IOP lowering surprisingly was unclear. While there were several similarities between the two trials, there were major differences, such as including of pseudoexfoliative and pigmentary glaucoma in EPGS. Unlike in the OHTS, participants randomized to treatment received dorzolamide as monotherapy, which may not be optimal as a standalone treatment. Nevertheless, the EGPS did find that higher IOP in both treated and untreated subjects was significantly associated with the development of glaucoma.

The second phase of the Ocular Hypertension Treatment Study (OHTS 2), determined if there is a penalty for delaying treatment in ocular hypertensives.¹² After a median of 7.5 years without treatment, the observation group received medication for a median of 5.5 years. At a median follow-up of 13 years, the cumulative proportions of participants who developed POAG in this group were compared to in original medication group. The results showed early medical treatment (20% IOP lowering) decreased the cumulative incidence of POAG by approximately 25%. While absolute reduction was greatest among participants at the highest baseline risk of developing POAG, there was little benefit of early treatment in low risk patients.

More Recent clinical trials, and follow-up studies

UK Glaucoma Treatment Study (UKGTS)

UKGTS was the first randomized placebo-controlled trial on newly diagnosed (previously untreated) patients with OAG and compared the outcome of patients treated with Latanoprost versus observation.¹³ The main advantage of this pivotal study was that data were acquired according to novel protocols optimized for the analysis of deterioration rate and could detect the differences in progression in only 2 years. The results demonstrated that treatment with latanoprost was effective in reducing IOP (3.8 mmHg in the latanoprost group versus 0.9 mmHg in the placebo group) and that the treated group had significantly fewer VF changes after 24 months.

Ocular Hypertension Treatment Study (OHTS) 3

In a recent report of OHTS (OHTS 3) 45.6% of the participants developed POAG in one or both eyes over 20 years of follow-up.¹⁴ A substantial proportion (~20%) of ocular hypertensive patients who developed POAG had rapid rates of VF loss in one or both eyes.¹⁵ This emphasizes that ocular hypertensive patients require careful follow-up, especially those at high risk of developing POAG to ensure early diagnosis and appropriate treatment of POAG. As mentioned, the study chose a 20% reduction in IOP for a treatment goal in OHTS as a proof of concept that lowering IOP could delay or prevent the onset of POAG. The mean IOP during follow-up of POAG participants in the present study was 18.4 mmHg. Currently, most clinicians would consider an IOP of 18 mmHg as inadequate in patients with progressive disease and would pursue more substantial reductions in IOP.

Treatment of Advanced Glaucoma Study (TAGS)

The Treatment of Advanced Glaucoma Study (TAGS) was a multicenter, randomized controlled trial that compared primary medical treatment versus primary augmented trabeculectomy in patients with newly diagnosed, advanced OAG and the primary outcome was vision-related quality of life.¹⁶ A greater IOP reduction was observed in patients who underwent trabeculectomy compared to the medical therapy arm (12.4 mmHg vs 15.1mmHg). VF progression was slower in the trabeculectomy group, emphasizing role of consistent low IOP in advanced glaucoma for preventing progression, while quality of life was comparable between the two arms. The authors concluded that trabeculectomy can be considered a primary treatment option for patients with advanced glaucoma.

Limitations of clinical trials, shortcomings, or constraints

Although clinical trials in glaucoma have greatly enhanced our understanding of the role of IOP in disease progression and provided valuable insights into the natural history of glaucoma through untreated control arms, they are not without limitations.

One key issue is generalizability—trial participants are often carefully selected and may not reflect the broader, more diverse patient populations seen in everyday practice. For example, major trials such as the Ocular Hypertension Treatment Study (OHTS) and the Early Manifest Glaucoma Trial (EMGT) included predominantly well-adherent patients with regular follow-up, which may not mirror real-world adherence patterns. Additionally, clinical trials tend to have narrowly defined inclusion criteria and standardized treatment protocols, which may not account for the heterogeneity of glaucoma subtypes, comorbidities, or evolving treatment preferences in clinical settings. In EGPS and CNTGS, prostaglandin analogue, a typical first line therapy of glaucoma, was not used; therefore, the results might not be applicable in current practice. In OHTS, patients were enrolled when there IOP was ranged between 24 to 32 mmHg and the results might not be relevant if the IOP is higher than this range. Moreover, optical coherent tomography, the current standard for optic nerve imaging, was not available at the time that these studies were initiated; one might argue that some of the progressors already might have had RNFL defects (and glaucoma) at the time of study entry. Another shortcoming of RCTs is relatively short follow-up durations compared to the chronic nature of glaucoma.

In contrast, real-world data—though less controlled—offers insights into long-term outcomes, treatment, variability among patients, and patient adherence in routine practice. Such data complement clinical trial findings and help bridge the gap between research and clinical decision-making. In recent years, some investigators have validated the findings of clinical trials using real-world data. For example, the predictive performance of the OHTS-EGPS risk model has been externally validated across four population-based cohorts of adults with ocular hypertension, demonstrating reasonable accuracy in estimating the 5-year risk of developing OAG.¹⁷

To date, IOP is the only modifiable factor, but there might be others.

When applying clinical trials to clinical practice, a uniform treatment regimen is most likely not optimal for all patients. Moreover, the landmark studies certainly imply that lowering IOP is beneficial, but they do not suggest that it is the sole factor in glaucoma management, nor that IOP reduction is protective for each patient. It is clear that treatment should be individualized.

In virtually all major clinical trials, many glaucoma patients still experienced VF deterioration despite treatment.^{2, 5, 6, 9, 15} As an example, the EMGT showed that in eyes with glaucoma when IOP was lowered by an average of 25%, treatment was of benefit versus no treatment. However, 45% of the treated group showed progressive VF loss. On the other hand, 38% of the control group were stable over the 6 years of follow-up.⁵

Several population-based studies, including the Barbados Eye Study^{18, 19} and the Los Angeles Latino Eye Study, have demonstrated an association between reduced ocular perfusion pressure and an increased risk of developing glaucoma. These findings suggest that vascular factors may play a significant role in glaucoma pathogenesis, particularly in patients with normal-tension glaucoma. More recently, other studies using optical coherence tomography angiography (OCTA) have also shown that reduced vessel density at the optic nerve head is a risk factor for both the development and progression of glaucoma.^20–22

Mechanisms of intraocular pressure-related injury

In the physiologic state, IOP is carefully regulated to maintain the stable ocular coat required for the pristine optics needed for vision. This internal loading force is counterbalanced externally by retroorbital sheath pressure at the optic nerve head, along with orbital pressure posteriorly, and atmospheric pressure anteriorly. The balance between these three forces defines the load under which the ocular coat is maintained. Alterations in this balance has profound impact on the load bearing connective tissues of the ONH, along with the overlying neurovascular tissues of the ONH and retina they support. (Figure 1)

Figure 1. Mechanobiolology of the Optic Nerve and Retina:

Increased Intraocular pressure (IOP) is counterbalanced by optic nerve sheath pressure (ONSP) resulting in tissue strain in the optic nerve head (ONH). This can damage axons directly, reduce focal perfusion, and activate cellular mechanotransduction that drives remodeling of the ONH. This remodeling alters ONH morphology and stiffness creating a negative feed back loop (−) that increases the vulnerability of the retinal ganglion cell (RGC) axons to further glaucomatous injury. Additionally, RGC somal injury can occur when IOP elevation reduces ocular perfusion pressure, which occurs most often with acute IOP elevation a function of IOP and blood pressure (BP), beyond the capacity for retinal autoregulation.

The effect of IOP on the optic nerve head

At the level of the optic nerve head, alterations in these pressure gradients cause local deformation (strain) impacting all cell types within the ONH and their blood supply. Human and animal studies have demonstrated that IOP-induced tissue deformation may directly injure cells, alter perfusion, and initiate mechanosensitive and inflammatory pathways that drive remodeling of the optic nerve. As with any load bearing structure, the degree of strain under a given load is dependent on the structure’s morphology and material properties²³. Since IOP-driven, mechanosensitive remodeling of the lamina cribrosa and sclera due to aging and glaucoma alters both ONH morphology and material properties, these cellular responses modulate how these tissues deform with changing pressure. This creates a self-reinforcing cycle that may explain the increase vulnerability of the ONH seen with aging and disease²⁴.

Several computational and experimental studies have emphasized the role of ONH biomechanics in the pathogenesis of axogenic retinal ganglion cell (RGC) injury in both acute IOP elevation and chronic glaucoma²⁵. Acute deformation of the ONH may cause axonal injury through direct and indirect mechanisms. The axons within the ONH can be directly injured due to physical stretch within the prelaminar neurovascular tissue or compression and/or shear within or adjacent to the lamina cribrosa (LC)²⁵. Indirectly, axonal injury can occur as a result of reduced ONH perfusion during acute IOP elevation. Reduced perfusion can occur within the ONH prelaminar region and neuroretinal rim²⁶, which is supplied by branches from the central retinal artery, and it can also occur at the LC itself, which is supplied by intra-scleral branches of the short posterior ciliary arteries, which are incased in load bearing connective tissues. Tissue stretch also activates mechanotransduction. While this drives chronic glaucomatous LC remodeling, it also follows acute IOP elevation, generating an inflammatory response through elevated glial reactivity²⁷.

Injury due to acute IOP elevation and chronic glaucoma in humans exhibits a consistently similar pattern of regional damage, which, thus far, appears unique among mammals²⁸. While never directly examined in the human eye in either acute or chronic disease, this pattern is thought to occur due to regional differences in axonal injury within the collagenous LC where regions of highest vulnerability to glaucomatous injury correspond to regional variations in connective tissue support (LC beam density)²⁹. These regional differences may result in greater strain-induced changes in perfusion, mechanical compression, mechanosensitive remodeling, and inflammatory responses within the deep load bearing structures of the ONH and/or the overlying neurovascular tissues they support. This regionality of glaucomatous injury supports the theory that IOP related axonal injury at the level of the ONH is a critical early mechanism of injury in both acute and chronic disease.

The effect of IOP on the neurosensory retina

The cellular responses of the neurovascular retina to changes in IOP are complex and integral to the pathophysiology of acute and chronic glaucomatous disease³⁰. Recent rodent models have demonstrated that even transient (0.5 – 1-hour) IOP elevations result in RGC dysfunction and may initiate pathways that predispose the retina to further IOP-related injury^31–34. Emerging data from research consented brain dead organ donors suggest that similarly brief IOP elevation may be sufficient to alter transcription within the human retina³⁵.

While lower levels of strain are experienced within the retinal tissues compared to the ONH in response to changes in IOP, the retinal vasculature is altered in both acute IOP elevation and in chronic glaucoma. Retinal blood flow is tightly regulated by local neural activity (neurovascular coupling) and is autoregulated across broad swings in ocular perfusion pressure. Prior studies in humans have shown that in most individuals with normal blood pressure (BP) the retina maintains steady perfusion up to a pressure of around 30 mmHg^{36, 37}. However, at pressures greater than 45 mmHg most individuals will experience regional capillary perfusion deficits. Thus, acute IOP injury may have an additional direct ischemic component if the pressure elevation and resultant change in ocular perfusion pressure is sufficient to overcome the autoregulatory capacity of the retina.

While the insult from acute IOP elevation differs from chronic glaucomatous injury, these initial molecular changes that occur after transient IOP elevation are relevant to RGC degeneration in the context of glaucoma because: 1) they underlie the pathogenesis of ischemic and glaucomatous retinal and optic nerve injury seen with acute angle closure and other forms of acute glaucoma; 2) the acute cellular responses predispose the retina to further IOP related injury^31–34; and 3) several of these acutely activated pathways are also active in chronic glaucoma.

While it is clear that there is a direct impact of acute changes in IOP on the retina, it is unclear whether the retinal changes in chronic glaucoma are due to axogenic injury at the ONH with secondary retina injury or there are additional direct and secondary pathways that may result in retinal injury due to chronic IOP-induced retinal neurovascular strain.

The therapeutic potential to modify how the eye responds to IOP

While the only current proven strategies to modify the course of glaucomatous disease is the lowering of IOP, there has been longstanding interest in developing therapies beyond IOP lowering, most often focused on neuroprotection of the RGCs to increase resilience. By understanding the molecular and cellular responses in the optic nerve and retina to tissue stretch, we can develop strategies to modulate these mechanovascularly-driven remodeling and inflammatory responses. This can potentially alter the strain experienced in these tissues, retard pathologic remodeling of the lamina cribrosa, and develop a more supportive milieu for the retinal ganglion cells and their axons.

Controversies

Idea behind target IOP

Target IOP is a useful clinical concept in a chronic disease requiring long-term treatment. It is defined as the IOP that minimizes the risk of glaucoma progression (with minimum impact on quality of life). Several clinical trials have used target IOP based on percent reduction from the mean baseline IOP or an absolute number depending on the stage of disease. However, there are some limitations on using ‘target IOP’ in the clinic. Our phenotyping of any particular patient is inherently limited, meaning that different patients who seemingly have similar risk profiles may have different susceptibility for further glaucoma progression. Another limitation is that our clinical measurements simply do not reflect the dynamic fluctuation of IOP.

Although the use of a target IOP is not mandatory in clinical practice and the scientific evidence³⁸ supporting this concept is not yet fully conclusive, it can serve as a useful ‘road map’ for clinicians to track IOP measurements over years of follow-up.^{6, 10} When using target IOP, clinicians should recognize that it is not a fixed value, and follow-up findings may lead to its re-estimation.

IOP has dynamic nature: Fluctuation

Traditional IOP measurements obtained during an office visit are often taken at a single point in time, akin to a ‘snapshot’, and provide a limited view of a patient’s 24-hour IOP profile.³⁸ Sleep studies have shown that nocturnal IOP is greater than diurnal IOP.³⁹ Thus, the singular readings in clinic fail to provide any information on nocturnal IOP or diurnal IOP fluctuation, and they can miss true peak IOP levels over 60% of the time.

While diurnal variation has been shown to be associated with glaucoma progression, independent of average IOP, the importance of assessing long-term IOP fluctuations remains controversial. Conflicting study results may be attributed to differences in the definition of long-term fluctuation, analytical methods, and study populations. For example, OHTS⁴⁰ and the EMGT study⁴¹ did not find any association between IOP variability and the development of glaucoma in eyes with untreated ocular hypertension and untreated glaucoma patients, respectively, while mean IOP was found to be associated. On the other hand, the AGIS, for instance, found that long-term IOP fluctuation was a significant and independent predictor of VF deterioration.⁴² This finding was further evaluated by a subsequent analysis, which revealed that the effect of IOP fluctuation was greater in patients with a low mean IOP (10–12 mmHg), whereas IOP fluctuation did not predict VF progression in the high mean IOP group (mean IOP, >16 mmHg).⁴³ One might speculate that long-term variability disrupts homeostatic mechanisms. As opposed to static stress, irregular and large fluctuations in IOP may cause loading and unloading of stresses, causing damage to the retinal tissue.⁴⁴ Recent studies have been shown that long-term IOP variability is independent association with glaucoma structural progression regardless of severity at baseline, even after adjustment for mean IOP.^{45, 46}

Some recent clinical trials, such as such as the Laser in Glaucoma and Ocular Hypertension Trial (LiGHT)⁴⁷ and HORIZON⁴⁸ studies, have also emphasized the importance of consistent IOP control for preventing glaucoma progression. In the 5-year follow-up report of the HORIZON clinical trial, VF progression was slower after combined cataract surgery and Hydrus implant compared to cataract surgery alone. However, the average daytime IOP in the combined arm was only slightly better (<1 mmHg) than cataract surgery alone group, and this difference would explain only a small proportion (17%) of the observed variation in glaucoma progression between the 2 arms. A recent 6-year report from the LiGHT trial also confirmed these findings. In the group initially treated with SLT, 70% of eyes maintained IOP at or below the target without requiring medical or surgical intervention, and fewer eyes showed disease progression compared to those initially treated with IOP-lowering eye drops (20% vs. 27%).⁴⁹ The more favorable outcomes seen in the LiGHT and HORIZON Trials might be attributed to more consistent IOP control achieved with SLT and the Hydrus Microstent, respectively, whose outflow effect is less influenced by medication adherence or dosing gaps, such as during sleep.

Glaucoma Progression and IOP: Evidence of a Nonlinear Effect

In contrast to EMGT,⁵ the CIGTS study demonstrated that when IOP was substantially reduced (by over 35% in both the surgery-first and medication-first groups), further reductions in IOP may not have a critical impact.⁶ On a real-world data, the effect of IOP showed a quadratic relationship with rates of VF loss.⁵⁰ Similarly, a recent post hoc analysis of UKGTS data demonstrated an exponential increase in the rate of VF loss as IOP rises, with the progression rate approximately doubling for every 10 mmHg increase in IOP. For example, if a patient with an average IOP of 10 mmHg progress with a VF rate of −0.5 dB/year, the average rate would increase to --1.0 dB/year at 20 mmHg. However, a further 10 mmHg (30 mmHg), would be catastrophic and increase the rate to −2.00 dB/year.⁵¹

Conclusion and future directions

IOP remains the primary modifiable risk factor in the management of glaucoma, and its reduction is the cornerstone of current treatment strategies. However, a subset of patients continues to progress despite achieving target IOP levels with medications or surgery. This has prompted ongoing research into the dynamic and circadian nature of IOP, as well as the role of IOP-independent mechanisms, such as impaired ocular blood flow and vascular dysregulation.