Optimizing topical glaucoma treatment outcomes: When less is better. A review on the clinical benefits of reducing treatment burden in glaucoma management

Abstract

Glaucoma, a leading cause of irreversible blindness, is primarily managed by lowering intraocular pressure, yet treatment remains limited by poor adherence, ocular surface toxicity, and systemic adverse effects. This review focuses specifically on treatment simplification strategies in topical glaucoma therapy, exploring the paradigm shift towards a “Less is better” approach in glaucoma care, with particular emphasis on the use of preservative -free formulations, lower active ingredient concentrations, and fixed combinations. These approaches aim to improve treatment tolerability, adherence, and clinical outcomes while minimizing toxicity, complexity, and environmental burden. Although barriers such as higher costs and limited long-term data remain, this new approach represents a patient-centred, sustainable, and clinically effective model for the future of glaucoma management.

Keywords

glaucoma preservative-free low concentration fixed combination ocular hypertension adherence ocular surface sustainability

Introduction

Glaucoma is characterized by a progressive loss of retinal ganglion cells and is the second leading cause of the global blindness in people aged over 50 years old in 2020.¹ Approximately 76–80 million people are currently living with this disease globally, with 12.3 million cases in Europe.² Glaucoma is projected to affect approximately 111.8 million people worldwide by 2040.³ Elevated intraocular pressure (IOP) is a significant risk factor for glaucoma progression, and lowering IOP is to date the only proven way to slow disease progression.⁴ Treatment options to reduce IOP include eye drops, laser procedures, and surgical interventions.^5,6 The first-line medical approach typically involves topical treatment monotherapy, but a significant proportion of patients require a combination of two or more medications to achieve target IOP and prevent or delay optic nerve damage. Prostaglandin analogues, the most effective IOP-lowering agents,⁷ are often combined with other drug classes such as β-blockers, carbonic anhydrase inhibitors, rho-kinase inhibitors, or α₂-adrenergic agonists.⁸

Long-term success in glaucoma therapy depends on both treatment efficacy and patient adherence. However, adherence was shown to be low in glaucoma patients,⁹ often due to adverse effects (AEs) or complex drug regimen associated with conventional therapies.¹⁰ Ocular surface disease (OSD) is more common in individuals with glaucoma than in the general population, making treatment tolerance a key factor when choosing suitable IOP-lowering medications.¹¹ Recent evidence indicates that a higher number of topical medications worsen meibomian gland obstruction severity, further contributing to ocular surface compromise and discomfort.¹² Evidence showed that poor glaucoma treatment adherence significantly accelerated visual field loss,¹³ highlighting the importance of consistent treatment to prevent disease progression. The prolonged use of preserved formulations, especially those with benzalkonium chloride (BAK), has been linked to eye surface toxicity, inflammation, and discomfort, which can negatively impact patient adherence.^14,15 Increasing studies have highlighted better adherence with preservative-free (PF) formulations compared to preserved ones.^16,17 Additionally, the complexity of using multiple medications and the risk of systemic absorption of active ingredients can cause AEs and treatment fatigue, further compromising patient adherence and the success of therapy.¹⁸

In response to these challenges of long-term topical therapy, a shift toward treatment simplification approaches consisting in simplified regimens has gained traction in ophthalmology leading to the concept of “Less is better”. This strategy simplifies treatment to enhance adherence, tolerance, and long-term outcomes.^19,20 Key measures include PF formulations, lower drug concentrations, fixed combinations, or reducing the number of instillations with fixed combinations or new innovative formulations to decrease ocular toxicity and treatment burden without compromising IOP control. Focusing on topical treatments, this review examines how these elements can affect the efficacy, tolerance, quality of life, and environmental sustainability of topical glaucoma therapies.

Methods

A narrative literature review was conducted in February 2025 to summarize current evidence on treatment simplification strategies in topical glaucoma therapy. PubMed searches combined disease terms (glaucoma), preservatives (preservat* OR BAK OR benzalkonium OR phosphate*), and treatment or dose strategies (monotherapy OR combination OR switch* OR “fixed combination” OR “low dose” OR dose reduc* OR “lower dose” OR “lowering dose”). Embase searches used Emtree and free-text terms for disease (‘glaucoma’/mj OR ‘chronic glaucoma’), dose modification (‘drug dose reduction’/exp OR ‘dosage decrease’ OR ‘dose reduction’ OR ‘drug tapering’), preservatives (‘preservative’/exp OR ‘phosphate’/exp), and combination therapy (‘fixed combination’). Only human studies reporting clinical trials, observational studies, guidelines, or systematic reviews were included, with no date restrictions applied. A total of 1,114 articles were retrieved. Relevant articles were screened by two independent reviewers, and studies addressing clinical efficacy, safety, adherence, or environmental impact of simplified glaucoma therapy were included. Exclusion criteria were non-topical interventions, studies lacking clinical or adherence outcomes, or insufficient methodological detail.

Clinical issues: Limitations of current treatments

Despite advances in glaucoma therapy, important limitations persist. These include preservative-related ocular toxicity, AEs related to active ingredients, and burden of complex multi-drug regimens (Figure 1).

Figure 1.

Overview of clinical limitations in current glaucoma therapies.

Figure 2.

Treatment simplification approaches in glaucoma management: scientific rationale and global impact.

Toxicity of preservatives

Impact on the ocular surface and deeper tissues

In glaucoma therapy, the chronic use of preservatives, particularly BAK, has been extensively linked to ocular surface toxicity, chronic inflammation, and disruption of homeostasis.^21–23 BAK can damage the corneal and conjunctival epithelium, impair tear film stability, and reduce goblet cell function, which may decrease treatment adherence.^24–28 These effects are especially pronounced in patients receiving multiple preserved medications, resulting in reduced treatment adherence and increased use of artificial tears.^20,29 Recent findings also suggest that BAK may disrupt the ocular surface microbiota, contributing to further instability and inflammation.^30–33 Beyond the ocular surface, BAK has been shown to penetrate deeper tissues and contribute to trabecular meshwork degeneration by increasing matrix metalloproteinase-9 activity and activating Müller glial cells.^34–38 Taken together, these processes trigger inflammatory cascades that may impair aqueous outflow, compromise IOP regulation, and potentially accelerate glaucoma progression.^39–42

Increased surgical risk and risk of surgical failure

Studies have shown that long-term exposure to preserved medications significantly increased the risk of surgical failure in glaucoma patients, likely due to ocular surface toxicity and reduced medication tolerance.^25,43 Indeed, in a nationwide cohort of 664,494 patients followed for a median of 4.8 years, the group using preserved eyedrops had more than a fourfold increased risk of undergoing glaucoma surgery compared to patients using PF drops, while patients using a mix of both had almost a twofold increased risk.⁴⁴

On the other hand, preoperative exposure to BAK-preserved medications has been associated with a higher risk of trabeculectomy failure.⁴⁵ Additionally, another study showed that eyes with higher ocular surface inflammation scores showed shorter postoperative survival and worse outcomes (p ≤ 0.03).⁴⁶ This increased failure rate is likely due to chronic subclinical inflammation and conjunctival remodelling, resulting in fibroblast activation and subconjunctival fibrosis in eyes previously exposed to preservatives.^47,48

Adverse effects linked to the active molecule

Ocular adverse effects

The primary goal of glaucoma treatment is to preserve the patient's visual function and quality of life at a sustainable cost, balancing both therapeutic efficacy and the burden of treatment.¹¹ IOP-lowering drugs currently available include prostaglandin analogues/prostamides, β-adrenergic receptor antagonists, carbonic anhydrase inhibitors, α-adrenergic receptor agonists, and Rho kinase inhibitors^5,11 (Table 1). While effective at lowering IOP, these drugs present a spectrum of ocular AEs described in Table 1,^11,18,49,51 especially in patients using multiple medications over the long term.⁵² Generally well tolerated, prostaglandin analogues/prostamides can cause local side effects including conjunctival hyperaemia, burning or stinging, and increased pigmentation of the iris and periocular skin.¹¹

Table 1.

IOP-lowering drugs used in glaucoma and corresponding adverse effects.

Drug category	Mechanism of action	Adverse effects	Reference
Prostaglandin analogues / Prostamides	Increase uveoscleral outflow	Ocular: conjunctival hyperaemia, burning stinging, foreign body sensation, itching, Minimal systemic effects	^11,15,49,50
β-adrenergic receptor antiagonists	Decrease aqueous humour production	Ocular: minimal ocular effects Systemic: cardiovascular and respiratory risks	^{11,15,49–51}
Carbonic anhydrase inhibitors (topical and oral)	Decrease aqueous humour production	Ocular: burning, visual disturbances Systemic (oral): fatigue, depression, electrolyte imbalances, rare severe reactions	^11,15,49,50
α-adrenergic receptor agonists	Decrease aqueous humour production and increase uveoscleral outflow	Ocular: burning, allergic conjunctivitis Systemic: sedation, dry mouth, hypotension	^11,15,49,50
Rho kinase inhibitors	Increase trabecular outflow	Ocular: conjunctival hyperaemia, congestion, and haemorrhage Generally well tolerated systemically	^11,15,49
Parasympathomimetics / Cholinergic agents	Increase trabecular outflow via ciliary muscle contraction	Ocular: miosis, ciliary spasm, brow ache, night vision issues Systemic: GI disturbances, CNS effects, hypotension	^11,15,49

Systemic adverse effects

Systemic risks from IOP-lowering medications can be important, particularly with long-term use and high active ingredient concentrations (Table 1).⁵⁰ These risks vary by drug class and must be considered, especially in patients with comorbidities. Overall, it is now well established that patients who experienced AEs reported higher levels of non-adherence than those who did not (37.6% versus 18.4%; p = 0.004).⁵³ Since poor treatment adherence leads to poor IOP control,⁵⁴ the lowest effective concentration providing the target therapeutic effect while minimizing AEs should be used.⁴⁹

Problems related to dosing regimens

Difficulty of adherence

According to the European Glaucoma Society Guidelines, glaucoma treatment typically starts with monotherapy. If it does not effectively lower IOP or is not well tolerated, another monotherapy or a combination therapy can be considered.¹¹ A real-world study in Portugal found that, despite the availability of fixed combinations, a significant portion of patients with glaucoma continued to be prescribed separate medications, resulting in unnecessarily complex regimens.^55,56 Indeed, nearly one-third of patients on dual therapy were using two individual eye drops, and almost 30% were administering three or more drops daily. Since fixed combinations combining a prostaglandin analogue and a β-adrenergic receptor antagonist require only a single daily drop, their broader use could have immediately reduced drop burden in over 10% of patients.⁵⁶ These findings underscore how optimizing treatment with fixed combinations can meaningfully reduce the number of daily administrations. Using multiple separate medications has been associated with poor adherence due to increased treatment complexity, frequency of dosing, and cumulative AEs, particularly when preserved formulations were involved.⁵⁷ Several studies reported higher rates of missed doses and treatment discontinuation with non-fixed regimens.^58–60 Finally, a patient-reported non-adherence study showed that for approximately one-third of patients, nonadherence with glaucoma therapy was a significant obstacle to therapeutic success.⁵³

Influence on the efficacy and progression of glaucoma

Poor adherence and inconsistent medication use, particularly with complex or burdensome regimens, can lead to suboptimal IOP control. Clinical studies have consistently shown that effective IOP reduction remains the only proven strategy to delay disease progression and preserve visual function.^61–64 When monotherapy fails to achieve adequate IOP control, persistent elevated IOP may contribute to progressive retinal ganglion cell loss, leading to visual field deterioration, impaired quality of life, and, eventually irreversible blindness.^62,65 Therefore, early recognition of treatment insufficiency and simplification of complex regimens, such as switching to fixed combinations, can play a critical role in improving adherence, especially since good adherence during the first year predicts continued long-term adherence, enhancing tolerability, achieving stable IOP, and preventing long-term visual impairment.⁶⁶

Changing the paradigm: Towards a treatment simplification approach

Given the challenges faced by both ophthalmologists and patients in managing glaucoma, including preservative toxicity, AEs from higher concentration of active ingredients, and the frequent need for multiple medications, simplified approaches have become increasingly relevant to improve glaucoma care (Figure 2).

Scientific foundations

Preservative-free versus preserved drugs

It is now well established that PF glaucoma medications can provide IOP reduction comparable to preserved formulations, while offering significantly improved ocular surface tolerance.⁶⁷ Clinical studies have consistently demonstrated that PF prostaglandin analogues, such as latanoprost,^68–70 bimatoprost 0.03% solution,⁷¹ bimatoprost 0.01% gel,^72,73 travoprost,⁷⁴ and tafluprost,^75,76 are non-inferior in lowering IOP compared to their preserved counterparts. This was also the case of PF versus preserved β-adrenergic receptor antagonists,⁷⁷ which led to fewer changes on ocular surface than preserved treatments.⁷⁸ These efficacy data were associated with improved tolerability in terms of conjunctival hyperaemia and better ocular surface outcomes.^{20,73,79–81} Moreover, switching from the preserved to the PF prostaglandin analogue improved tear film stability and tear film breakup time, and reduced corneal staining and conjunctival hyperaemia.^82–84 Interestingly, even preservative-optimized formulations, such as sofZia, Polyquad, or formulations containing less toxic preservatives, may represent transitional options when PF alternatives are unavailable or cost-prohibitive.^21,23,85

Concentration of active ingredients

The evolution toward lower concentrations in ocular hypotensive treatments marks a major advance in glaucoma care, driven by the need to maintain efficacy while improving treatment tolerability. This shift began in the early 2000s with timolol 0.1% gel, the first low-concentration timolol gel formulation, allowing a prolonged residence time onto the ocular surface. It achieved a similar IOP-lowering effect as timolol 0.5% aqueous solution while significantly reducing systemic side effects and enabling a simplified dosing regimen from twice daily to once daily.^86–92

Bimatoprost 0.03% was reformulated to improve tolerability, first as a preserved 0.01% formulation, and later as a 0.03% PF formulation, both of which displayed non-inferior efficacy while reducing conjunctival hyperaemia and ocular discomfort.^93–98 The next step was the development of bimatoprost 0.01% PF gel, combining lower bimatoprost concentration with an innovative gel base.⁷³ This gel differs from the previous one because it relies on the patented FDGt^®—a fluid and gel technology combining three key ingredients: carbomer to enhance viscosity, sodium acetate trihydrate as viscosity-adjusting agent, and macrogol to improve solubility.⁹⁹ Compared to preserved bimatoprost 0.01%, bimatoprost 0.01% PF gel showed a lower incidence and less worsening of conjunctival hyperaemia at both week 6 (20.1% vs. 29.3%) and week 12 (18.3% vs. 30.4%), with non-inferior efficacy.⁸⁴ A phase III study conducted in the USA further confirmed these results. Indeed, bimatoprost 0.01% PF gel was noninferior to preserved bimatoprost 0.01% in IOP-lowering over 12 weeks, with fewer ocular AEs (28.1% vs. 34.8%) and less conjunctival hyperemia at Week 12 (54.8% vs. 63.2%) compared to preserved bimatoprost 0.01%.¹⁰⁰ Pharmacokinetic data confirm that the gel prolongs ocular contact time, enabling effective IOP control at lower concentrations.⁸³ Indeed, preclinical results demonstrated that PF bimatoprost 0.01% gel showed higher ocular exposure compared to preserved bimatoprost 0.01% (C_max: 50.2 versus 26.3 ng/mL; AUC_0.5−8h: 134.0 versus 67.0 ng·h/mL) and similar to preserved bimatoprost 0.03% (C_max: 59.9 ng/mL; AUC_0.5−8h: 148.0 ng·h/mL). In healthy humans, systemic exposure to bimatoprost was lower for the PF 0.01% gel (0.5248 and 0.5645 ng·min/mL on Days 1 and 15) than for the preserved 0.01% formulation (0.8461 and 0.7551 ng·min/mL), with no systemic accumulation observed in either group.⁸³ This further highlights that lowering treatment concentration may improve tolerability and subsequent adherence to medication. Taken together, these advances underscore the role of innovative formulations (i.e., gel formulations) in achieving low-concentration efficacy with better tolerability, thereby addressing key needs in glaucoma management.

The first fixed combination of bimatoprost 0.03% and timolol 0.5% was initially launched in 2006 as a multi-dose formulation and later as a PF single-dose version. More recently, PF fixed combination of bimatoprost 0.01% and timolol 0.1% has emerged as the first PF low concentration fixed combination therapy incorporating gel formulation technology. Phase II clinical pharmacokinetic results demonstrated significantly lower systemic concentration of timolol after 12 weeks with PF bimatoprost 0.01%/timolol 0.1% gel compared to other combinations containing higher timolol concentrations.¹⁰¹ Regarding safety, treatment-related ocular AEs were generally mild to moderate, occurring in 13.8% of patients treated with PF bimatoprost 0.01%/timolol 0.1%, and in 21.4% of patients receiving PF bimatoprost 0.03%/timolol 0.5%.¹⁰¹ In a Phase III study, PF bimatoprost 0.01%/timolol 0.1% gel was compared to PF bimatoprost 0.03%/timolol 0.5% ophthalmic solution, showing non-inferior efficacy and a favourable safety profile.¹⁰² Indeed, no patient discontinued PF bimatoprost 0.01%/timolol 0.1% gel due to AEs, while a 2.9% discontinuation rate was reported with PF bimatoprost 0.03%/timolol 0.5% ophthalmic solution.¹⁰² Overall, these findings emphasize that innovative fixed combinations, particularly low-concentration gel formulations, can achieve effective IOP reduction with improved tolerability, thereby supporting adherence and addressing important needs in glaucoma management.

Fixed versus non-fixed combination

Fixed combination medications are a valuable option in glaucoma management, particularly when monotherapy failed to provide sufficient IOP reduction.¹¹ Numerous studies supported the efficacy of various fixed combinations in IOP reductions.^{100,103–106} The first fixed combination of bimatoprost 0.03% and timolol 0.5% demonstrated non-inferior IOP-lowering efficacy than non-fixed combination and was particularly effective in patients insufficiently controlled on prostaglandin analogue monotherapy. Interestingly, the fixed combination had better safety profile than individual components alone.^107,108 At three months, mean diurnal IOP decreases ranged from 8.1 mmHg with fixed combination to 6.4–7.9 mmHg with bimatoprost or timolol alone. A higher proportion of patients on fixed combination achieved significant IOP reductions (>20%) and target pressures (<18 mmHg) compared to bimatoprost and timolol.¹⁰⁷ Importantly, fixed combination also showed a lower incidence of conjunctival hyperaemia than bimatoprost or non-fixed combinations, with rates ranging from 8.5% to 22.7%, compared to up to 38.5% in bimatoprost groups.^107,108 The improved safety profile of the fixed combination compared to individual components may be attributed to the complementary mechanisms of action and pharmacological interactions between the drugs. Combining bimatoprost and timolol in a single formulation allows for effective IOP reduction at potentially lower individual drug concentrations, which might reduce the incidence of side effects such as conjunctival hyperaemia. Additionally, timolol's β-receptor antagonist properties could mitigate some of the vasodilatory effects of bimatoprost, leading to decreased ocular redness. Russ et al. have shown that short-term use (three months) of fixed combinations of prostaglandin analogues (latanoprost, bimatoprost, and travoprost) with 0.5% timolol maleate could still adversely affect the ocular surface.¹⁰⁹ However, it is unsure if the treatments used in this study were preserved or not, and if this AE could be attributed to preservatives.¹⁰⁹ Given these data, there is a need for careful patient monitoring when using non-fixed or fixed combinations.

Clinical implications and therapeutic choices

Treatment adherence enhancement

PF glaucoma medications offer significant advantages in efficacy and patient experience, particularly for patients with OSD.^57,67,110 Despite challenges such as higher costs (see Section “Optimization of health costs”), they are advantageous for many patients, particularly those at risk of surgical intervention.^47,78 Switching to PF drops improved patient-reported outcomes, including quality of life, and sustained IOP control, making them ideal for personalized care, especially for patients with intolerance to preserved regimens.^{42,48,53,57,69} Low-concentration formulations can also reduce AEs and improve adherence,¹¹¹ as seen with timolol 0.1%, which has a better safety profile and patient acceptance (measured through the COMTOL questionnaire¹¹²) compared to timolol 0.5%.^89,113

On the other hand, fixed combinations could be beneficial for patients needing additional IOP-lowering therapy.^{106,114–116} By reducing administration frequency and dosing complexity, they improve adherence and overall patient experience.^117–120 Studies confirmed higher adherence with fixed combination therapies, especially PF ones, compared to non-fixed or preserved combinations.^121–125 Prostaglandin analogues/timolol fixed combinations showed better persistence and fewer discontinuations over time compared to separate agents.^126–132 In a randomized clinical trial comparing two PF fixed combination of bimatoprost with timolol, overall treatment tolerability was higher with the gel formulation than with the eye drops, with 96–97% of patients and 96% of investigators reporting very satisfactory or satisfactory tolerability.¹⁰² This new gel formulation may represent a more favourable alternative to existing treatment options, offering potential improvements in both patient compliance and sustained drug delivery. Combining timolol with prostaglandin analogues in fixed combinations generally improves tolerability by reducing common ocular side effects.^133–135 Fixed combinations also lower the risk of dosing errors, ensuring more consistent IOP management.¹²² Overall, available literature supports the concept that low-concentration PF fixed combinations provide a straightforward, reliable treatment option, helping to minimize treatment errors and improve adherence.

Quality-of-life improvement

In the context of treatment simplification approaches, improving patients’ quality of life goes beyond controlling IOP, since it involves minimizing treatment burden, AEs, and discomfort. While patients with early-stage glaucoma often retain good visual function, patients with advanced disease face significant declines in quality of life,¹¹ deepened by the inconvenience of complex regimens, medication intolerance, and financial strain.⁵⁷ Previous reports showed that switching to PF eye drops markedly improved treatment satisfaction^73,136,137 and visual-related quality of life by reducing ocular surface irritation, the need for artificial tears, and drop discomfort.^76,138–141 PF fixed combinations further enhance these benefits by simplifying regimens and limiting cumulative exposure to harmful agents such as BAK, which has been closely associated with OSD and reduced quality of life.^136,142 These improvements extend beyond subjective tolerability and may translate into better adherence, fewer treatment disruptions, and more stable long-term outcomes.^48,140 Thus, by reducing the toxic load and simplifying therapy, treatment simplification strategies support both clinical effectiveness and meaningful improvements in patients’ quality of life.

Sensitive populations

OSD is prevalent in glaucoma patients, especially due to long-term use of anti-glaucoma medications.^143–145 Preservatives, particularly BAK, are strongly linked to OSD development and worsening, with symptoms increasing over time and with the number of medications used. Mylla Boso et al. demonstrated that each additional BAK-containing eyedrop was associated with a twofold increase in the odds of abnormal lissamine staining, a tool to assess OSD.¹⁴⁴ Moreover, a recent survey found 45% of ophthalmologists see OSD in at least 25% of their patients, with redness (91.9%) and conjunctival hyperaemia (75.6%) as the most frequent symptoms.¹⁴⁶ BAK was identified as the main cause of OSD by 90% of respondents. To manage OSD, physicians frequently switched to PF medications (33.7%) or drops with alternative preservatives (20.4%). Most respondents also prescribed artificial tears (84.6%) to alleviate symptoms.¹⁴⁶ It is noteworthy that ocular surface treatment significantly improves visual acuity, OSDI scores, bulbar redness, and fluorescein staining, without having to stop IOP-lowering medication.¹⁴⁴

Elderly patients are more prone to both ocular surface irritation and systemic AEs, including cardiovascular complications.¹⁴⁷ Lower-concentration treatments, especially timolol, help avoid complications in this population of patients, who often face physical challenges that can alter proper medication use.¹⁴⁸ As mentioned in Section “Treatment adherence enhancement”, fixed combination therapies further support adherence. This is particularly the case in elderly or patients with motor or cognitive impairments, by reducing both the number of required eye drops and the dosing regimen from twice to once daily. Once-daily combinations such as latanoprost/timolol were more manageable for patients with limited dexterity, poor vision, or memory issues.¹⁴⁹ Simplifying regimens also helped prevent missed doses in patients taking multiple medications, which usually happens in elderly, supporting long-term disease control and easing caregiver responsibilities.^120,122

Beyond clinical benefits: Global impact of “Less is better”

Treatment simplification approaches in glaucoma management extend benefits beyond clinical outcomes. They may reduce the environmental impact, lower healthcare costs, and support more efficient prescription practices. This strategy could promote sustainability and enhance overall healthcare system efficiency.

Reduction of environmental impact

Less pollution due to preservatives

The release of toxic agents such as BAK into the environment was reported to lead to aquatic toxicity and environmental persistence. Indeed, when used as a disinfectant, BAK has been frequently found in various environmental mediums such as wastewater influent and groundwater.¹⁵⁰ Once in the environment, BAK can be lethal to aquatic organisms, disrupt local ecosystems and contribute to the broader issue of antimicrobial resistance.¹⁵⁰ Although direct data linking ophthalmic BAK use to environmental harm are limited, these findings suggest that reducing overall BAK usage may help lower environmental exposure. Transitioning to PF formulations could significantly reduce this environmental impact, benefiting both ecosystems and human health.

Reduction of plastic and pharmaceutical waste

In addition to the environmental concerns related to preservatives, the plastic and pharmaceutical waste generated by glaucoma medication packaging is another area where improvements can be made. A study in intensive care settings has shown that medication waste, particularly with intravenous drugs such as anaesthetics used for surgeries, was both substantial (over 10%) and largely unavoidable due to clinical complexity.^151,152 An anaesthesia study on surgery reported 45% of propofol waste, which could be reduced by using smaller vials, avoiding unnecessary drug disposal.¹⁵³ While these findings originate from non-ophthalmic settings, they illustrate the broader challenge of pharmaceutical waste across healthcare systems and provide a conceptual framework relevant to chronic diseases such as glaucoma.

Fixed combinations decrease the number of vials required for treatment, leading to a reduction in plastic waste, packaging, and energy costs associated with production and transport. Ophthalmic studies have highlighted that minimizing the number of medications not only simplifies regimens,¹⁵⁴ but may also align with sustainable healthcare practices by reducing the overall pharmaceutical burden on the environment.¹⁵⁵

On the other hand, multi-dose vials can significantly reduce the overall amount of plastic waste generated by glaucoma medications. For patients with glaucoma, multi-dose delivery systems have been proposed as a way to reduce plastic waste, and some evidence suggests they may also support adherence by simplifying administration compared to single-use containers.¹⁵⁶ These systems not only simplify the medication administration process but also provide an environmentally sustainable alternative to the traditional single-use plastic containers. However, despite these advances, certain innovative formulations, such as gel-based preparations, are not yet compatible with PF multi-dose bottles, and thus still require single-dose packaging to deliver their therapeutic effects.

Less carbon footprint with reduced medical travel

Multiple studies have shown that fixed combinations and PF formulations improve adherence, enhance tolerability, and reduce AEs (see Section “Changing The Paradigm”). As a result, patients on these better-tolerated therapies could be less likely to require additional clinic visits related to side effects or the need of therapy modification. A recent report identified patient and staff travel as the primary source of emissions within glaucoma care pathways.¹⁵⁷ Although a direct causal link between specific glaucoma therapies and carbon footprint reduction has not yet been formally established, improved treatment stability could potentially allow for longer follow-up intervals in selected patients. This approach may help maintain high-quality care while reducing the number of patient journeys, an especially relevant benefit in rural or underserved areas where access to ophthalmologists may involve long travel distances.

Optimization of health costs

Reduction of medical visits and supportive treatments

Previous studies have demonstrated that fixed combinations can improve patient adherence (see Section “Sensitive populations”), reduce the likelihood of medication-related complications, and may be associated with a lower frequency of follow-up visits^128,158 and improved quality of life. Fixed combinations were described as cost-effective treatment option for patients with glaucoma.^156,159 Brand-name combination medications were often less expensive than purchasing their individual components separately, further strengthening their cost-effectiveness.¹⁶⁰ In addition, improved adherence resulted in reduced overall costs over time. For example, switching from bimatoprost 0.03% to bimatoprost 0.01% led to cost savings after the initial years of treatment, with a lifetime reduction reaching US$3433.¹⁶¹

Furthermore, because preserved IOP-lowering medications are commonly linked to ocular surface disorders (see Section “Impact on the ocular surface and deeper tissues”), using PF therapies may reduce the need for additional treatments, including artificial tears.²⁰ In the UK, prescription costs for PF treatments increased significantly in recent years, but their benefits over the preserved alternatives could justify this rise, especially as patients experienced fewer complications and required less supplemental care.¹⁶²

Surgeries and their complications

A significant portion of healthcare expenditures in glaucoma management arises from surgical interventions, such as trabeculectomies and cataract surgeries, along with their associated complications. It has been demonstrated that optimizing medical therapy through the use of less concentrated, PF, and fixed combination eye drops can help control disease progression and delay or avoid surgical interventions.¹⁶³ Fewer surgeries would be expected to translate into fewer complications, reduced hospitalization, and lower expenditures on postoperative care and rehabilitation, factors particularly relevant in managing elderly patients and those with multiple health conditions.

Challenges and perspectives

The increasing focus on innovative glaucoma treatment strategies reflects a growing effort to improve patient adherence, comfort, and overall disease management. The higher cost of PF medications, driven by more complex manufacturing and packaging processes, remains a key factor influencing their wider adoption. This price gap between preserved and PF medications¹⁶⁴ has practical implications for healthcare systems and patients, often limiting access despite the known benefits of PF treatments in improving ocular surface health and treatment adherence.

In addition to cost, treatment optimization remains an ongoing concern. While fixed combination therapies reduce dosing complexity and can improve adherence, they inherently limit the flexibility to individually adjust medication components or timing. For some patients, particularly those with variable responses or specific tolerance issues, this lack of flexibility can delay optimal IOP control.⁶⁰ Using separate agents could allow therapy to be escalated only when necessary, supporting a stepwise, individualized approach that balances efficacy with the goal of limiting treatment burden. Furthermore, although combinations involving prostaglandin analogues are commonly used and generally effective and well tolerated, no single combination has proven universally ideal.¹⁶⁵ There is also continued debate over whether fixed combinations consistently outperform individually dosed regimens in terms of efficacy.⁸

Treatment simplification in glaucoma management is not limited to topical formulations alone. Selective Laser Trabeculoplasty (SLT) offers a cost-effective, non-invasive alternative that can be used as a first-line treatment.^11,166 By enhancing aqueous outflow, SLT effectively lowers IOP and may reduce or eliminate the need for daily topical medications, improving adherence and reducing the risk of medication-related AEs.^166,167 This treatment could offer a convenient alternative that supports long-term ocular health while reducing dependence on eyedrops. This not only simplifies disease management but may also contribute to long-term cost savings. Systemic treatments such as oral acetazolamide may also play a role in patients needing a rapid IOP reduction or when topical options are insufficient or poorly tolerated.¹⁶⁸ However, their long-term use is limited by systemic side effects. Beyond established therapies, emerging treatment modalities such as implants may be considered when adherence, treatment burden, and tolerability issues need to be addressed.

Another important barrier to broader use of PF and fixed combination therapies is limited physician awareness regarding their benefits. Many clinicians, particularly general practitioners who issue most prescriptions, may underestimate the toxic effects of common preservatives such as BAK on the ocular surface and patient comfort. National guidelines can further influence these trends. For instance, the Danish Guidelines restrict substitution with generics and explicitly encourage the use of PF formulations, illustrating how structured recommendations may help align prescribing practices with patient-centered outcomes.¹⁶⁹ These discrepancies underscore the urgent need for enhanced education and standardized prescribing guidelines to improve understanding of PF formulations and fixed combinations, ultimately optimizing patient outcomes.

Importantly, treatment simplification should also be applied to clinical decision-making and care delivery. Education of practitioners should be strengthened to support appropriate adaptation of treatment over time. Risk-stratified follow-up schedules and intentional de-escalation of therapy in stable disease may help avoid overtreatment while preserving visual function. However, it is important to note that minimalism does not imply undertreatment but rather refers to selecting the least burdensome regimen that achieves the patient's target IOP, with timely escalation to additional medical, laser, or surgical interventions when clinically indicated, particularly in advanced disease. New monitoring tools, including AI-based approaches for detecting glaucomatous progression, may further support individualized treatment decisions by identifying disease worsening earlier and more reliably.¹⁷⁰ This would contribute to treatment simplification in glaucoma care with the reduction of unnecessary testing and clinic visits.

Finally, a need for robust long-term evidence persists. While current data support short- and mid-term benefits such as better adherence, fewer AEs, and improved ocular surface outcomes (see Section “Changing the paradigm”), the long-term impact of these therapies on IOP control, disease progression, and visual outcomes remains insufficiently studied. Given the lifelong nature of glaucoma, future research must assess the durability of these benefits over time, as well as their cost-effectiveness and influence on quality of life.

PF fixed combination low-concentration therapies strongly support the goals of modern glaucoma management and successfully integrating them into routine care will be achieved by addressing economic, clinical, and evidence-based opportunities.

Conclusion

Treatment simplification approaches in glaucoma care allow a “Less is better” concept and promote simpler, safer, and more sustainable treatment strategies without compromising efficacy. By favouring PF and low-concentration formulations, it reduces AEs and improves patient comfort and adherence. Fixed combinations further streamline regimens, minimizing dosing errors and enhancing long-term IOP control, leading to better clinical outcomes. Environmentally, it reduces preservative contamination and plastic waste, while economically, it could lower long-term healthcare costs. Overall, this strategy supports a more patient-centred, efficient, and environmentally responsible model of glaucoma management.

Footnotes

Acknowledgements

The authors thank Marina SCHVERER, PhD (Laboratoires Théa) who provided medical writing assistance.

ORCID iDs

Ronald Marinus Petrus Cornelis de Crom

Luis Abegão Pinto

Jose Manuel Benitez-del-Castillo

Ethical considerations

Not applicable because no human participant were involved in the study.

Consent to participate

There are no human participants in this article and informed consent is not required.

Consent for publication

Not applicable.

Funding

This work was funded by Laboratoires Théa.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ronald M.P.C. de Crom has received consultancy and speaker fees from Abbvie, Thea Pharma, Santen, and Tramedico. Luis Abegão Pinto declares his position as consultant for Théa, Alcon, Abbvie, Santen, and Nidek. Ingeborg Stalmans has received grant or research support from Théa and Santen; clinical trial participation from Théa and Santen; honoraria or consulting fees from AbbVie, Elios, EyeD, Horus, Santen, and Théa; and is co-founder and shareholder of Mona. Andrew Tatham declares research support from AbbVie, Nova Eye Medical, iStar Medical; consultancy from Thea, Santen, Alcon, AbbVie, Viatris, Ciliatech, Regeneron; and is a speaker for Thea, Santen, Alcon, AbbVie, Viatris, Nova Eye Medical. Verena Prokosch reports no conflicts of interest. Miriam Kolko has served as a speaker for Santen, Allergan/Abbvie, Théa, Topcon, and ESW-Vision; has served on advisory boards for Allergan/Abbvie, Théa, Santen, EYE-GO, EarlySight, and Topcon; has received collaboration grants from Théa, Santen, and Zeiss; and has acted as consultant for Abbvie and Théa. Jose M. Benitez-del-Castillo reports receiving grants or personal fees from Théa, Santen, Alcon, Brill, B+L, Angelini, Nordic Pharma, and Faes.

Data availability statement

Not applicable.

References

GBD 2019 Blindness and Vision Impairment Collaborators* and Vision Loss Expert Group of the Global Burden of Disease Study†, on behalf of the. Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the right to sight: an analysis for the global burden of disease study. Lancet Glob Health 2021; 9: e144–e160.

Stuart

de Vries

Schuster

, et al. Prevalence of glaucoma in Europe and projections to 2050. Ophthalmology 2025; 132: 1114–1124.

Tham

Y-C

Wong

, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 2014; 121: 2081–2090.

Jayaram

Kolko

Friedman

, et al. Glaucoma: now and beyond. Lancet 2023; 402: 1788–1801. doi:10.1016/S0140-6736(23)01289-8

Mai

Ferguson

Radcliffe

. New treatments for glaucoma. Curr Opin Ophthalmol 2025; 36: 135–139. doi: 10.1097/ICU.0000000000001110

Sarkis

Chamard

Johansen

, et al. Challenging glaucoma with emerging therapies: an overview of advancements against the silent thief of sight. Front Med (Lausanne) 2025; 12: 1527319.

Lee

McCluskey

. Clinical utility and differential effects of prostaglandin analogs in the management of raised intraocular pressure and ocular hypertension. Clin Ophthalmol 2010; 4: 741–764.

Aptel

Chiquet

Romanet

J-P

. Intraocular pressure-lowering combination therapies with prostaglandin analogues. Drugs 2012; 72: 1355–1371.

Feehan

Munger

Cooper

, et al. Adherence to Glaucoma Medications Over 12 Months in Two US Community Pharmacy Chains. J Clin Med 2016; 5: 79–79. doi: 10.3390/jcm5090079

10.

Cvenkel

Kolko

. Current medical therapy and future trends in the management of glaucoma treatment. J Ophthalmol 2020; 2020: 6138132.

11.

Pazos

Traverso

Viswanathan

. European Glaucoma Society. European glaucoma society – terminology and guidelines for glaucoma, 6th edition. Br J Ophthalmol 2025; 109: 1–212.

12.

Tan

Yin

Wang

, et al. Analysis of risk factors associated with meibomian gland orifice obstruction severity in glaucoma patients: a clinical investigation. BMC Ophthalmol 2025; 25: 560.

13.

Newman-Casey

Niziol

Gillespie

, et al. The association between medication adherence and visual field progression in the collaborative initial glaucoma treatment study. Ophthalmology 2020; 127: 477–483. doi: 10.1016/j.ophtha.2019.10.022

14.

Aguayo Bonniard

Yeung

Chan

, et al. Ocular surface toxicity from glaucoma topical medications and associated preservatives such as benzalkonium chloride (BAK). Expert Opin Drug Metab Toxicol 2016; 12: 1279–1289.

15.

Zhou

Zhang

Zhou

, et al. A narrative review of ocular surface disease related to anti-glaucomatous medications. Ophthalmol Ther 2022; 11: 1681–1704.

16.

Kim

Lee

C-K

Shin

, et al. Comparison of efficacy and ocular surface assessment between preserved and preservative-free brimonidine/timolol fixed-combination eye drops in glaucoma patients: a parallel-grouped, randomized trial. J Clin Med 2025; 14: 1587.

17.

Kim

Shin

Lee

, et al. Comparison of ocular surface assessment and adherence between preserved and preservative-free latanoprost in glaucoma: a parallel-grouped randomized trial. Sci Rep 2021; 11: 14971.

18.

Balas

Mathew

. A review of ocular and systemic Side effects in glaucoma pharmacotherapy. JCTO 2025; 3: 2.

19.

Konstas

Schmetterer

Costa

, et al. Current and emerging fixed combination therapies in glaucoma: a safety and tolerability review. Expert Opin Drug Saf 2020; 19: 1445–1460.

20.

Economou

Laukeland

Grabska-Liberek

, et al. Better tolerance of preservative-free latanoprost compared to preserved glaucoma eye drops: the 12-month real-life FREE study. Clin Ophthalmol (Auckland, N.Z.) 2018; 12: 2399–2407.

21.

Kahook

Rapuano

Messmer

, et al. Preservatives and ocular surface disease: a review. Ocul Surf 2024; 34: 213–224.

22.

Kemer

ÖE

Mekala

Dave

, et al. Managing ocular surface disease in glaucoma treatment: a systematic review. Bioengineering (Basel, Switzerland) 2024; 11: 1010.

23.

Meloni

Pauly

de Servi

, et al. Occludin gene expression as an early in vitro sign for mild eye irritation assessment. Toxicol Vitro Int J Publish Assoc BIBRA 2010; 24: 276–285. https://pubmed.ncbi.nlm.nih.gov/19729060/ (2010) .

24.

Baudouin

Hamard

Liang

, et al. Conjunctival epithelial cell expression of interleukins and inflammatory markers in glaucoma patients treated over the long term. Ophthalmology 2004; 111: 2186–2192.

25.

Baudouin

Labbé

Liang

, et al. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retinal Eye Res 2010; 29: 312–334.

26.

Kahook

Noecker

. Quantitative analysis of conjunctival goblet cells after chronic application of topical drops. Adv Ther 2008; 25: 743–751.

27.

Mastropasqua

Agnifili

Fasanella

, et al. Conjunctival goblet cells density and preservative-free tafluprost therapy for glaucoma: an in vivo confocal microscopy and impression cytology study. Acta Ophthalmol (Copenh) 2013; 91: e397–e405.

28.

Prusek

Sikora

Skubis-Sikora

, et al. Assessment of the toxic effect of benzalkonium chloride on human limbal stem cells. Sci Rep 2025; 15: 12295.

29.

Fineide

Magnø

Dahlø

, et al. Topical glaucoma medications − possible implications on the meibomian glands. Acta Ophthalmol (Copenh) 2024; 102: 735–748.

30.

Kamdougha

Taminiau

Fall

, et al. Alterations of ocular surface microbiome in glaucoma and its association with dry eye. J Med Microbiol 2025; 74: 002013. doi: 10.1099/jmm.0.002013

31.

Gagliano

Salvetat

Musa

, et al. Bacterial insights: unraveling the ocular microbiome in glaucoma pathogenesis. Front Biosci (Landmark Ed) 2024; 29: 310.

32.

Aragona

Baudouin

Del Benitez Castillo

, et al. The ocular microbiome and microbiota and their effects on ocular surface pathophysiology and disorders. Surv Ophthalmol 2021; 66: 907–925.

33.

Labetoulle

Baudouin

Del Benitez Castillo

, et al. How gut microbiota may impact ocular surface homeostasis and related disorders. Prog Retinal Eye Res 2024; 100: 101250.

34.

Ammar

Kahook

. Effects of benzalkonium chloride- or polyquad-preserved fixed combination glaucoma medications on human trabecular meshwork cells. Mol Vision 2011; 17: 1806–1813.

35.

Barabino

Antonelli

Cimbolini

, et al. The effect of preservatives and antiglaucoma treatments on the ocular surface of mice with dry eye. Invest Ophthalmol Visual Sci 2014; 55: 6499–6504.

36.

Brignole-Baudouin

Desbenoit

Hamm

, et al. A new safety concern for glaucoma treatment demonstrated by mass spectrometry imaging of benzalkonium chloride distribution in the eye, an experimental study in rabbits. PloS one 2012; 7: e50180.

37.

Mohammed

Kulkarni

Faraj

, et al. Profiling ocular surface responses to preserved and non-preserved topical glaucoma medications: a 2-year randomized evaluation study. Clin Experiment Ophthalmol 2020; 48: 973–982.

38.

Tressler

Beatty

Lemp

. Preservative use in topical glaucoma medications. Ocul Surf 2011; 9: 140–158.

39.

Baudouin

Riancho

Warnet

J-M

, et al. In vitro studies of antiglaucomatous prostaglandin analogues: travoprost with and without benzalkonium chloride and preserved latanoprost. Invest Ophthalmol Visual Sci 2007; 48: 4123–4128.

40.

Pérez-Bartolomé

Martínez-de-la-Casa

Arriola-Villalobos

, et al. Ocular surface disease in patients under topical treatment for glaucoma. Eur J Ophthalmol 2017; 27: 694–704.

41.

Zhang

Vadoothker

Munir

, et al. Ocular surface disease and glaucoma medications: a clinical approach. Eye Contact Lens 2019; 45: 11–18.

42.

Dubrulle

Labbé

Brasnu

, et al. Influence of Treating Ocular Surface Disease on Intraocular Pressure in Glaucoma Patients Intolerant to Their Topical Treatments: A Report of 10 Cases - PubMed, https://pubmed.ncbi.nlm.nih.gov/30489502/ (2018, accessed 18 July 2025).

43.

Baudouin

Pisella

Fillacier

, et al. Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology 1999; 106: 556–563.

44.

Chamard

Bron

Roux

, et al. Association between preserved glaucoma eye drops exposure and glaucoma surgery occurrence: a nationwide 10-year outcome study. Ophthalmol Ther 2025; 14: 2543–2555.

45.

Boimer

Birt

. Preservative exposure and surgical outcomes in glaucoma patients: the PESO study. J Glaucoma 2013; 22: 730–735.

46.

Wong

JKW

Leung

Lai

JS-M

, et al. Evaluation of adverse effects of topical glaucoma medications on trabeculectomy outcomes using the glaucoma medications intensity Index. Ophthalmol Ther 2022; 11: 387–401.

47.

Baudouin

Kolko

Melik-Parsadaniantz

, et al. Inflammation in glaucoma: from the back to the front of the eye, and beyond. Prog Retinal Eye Res 2021; 83: 100916.

48.

Thygesen

. Glaucoma therapy: preservative-free for all? Clinical Ophthalmology (Auckland, N.Z.) 2018; 12: 707–717.

49.

Jaenen

Baudouin

Pouliquen

, et al. Ocular symptoms and signs with preserved and preservative-free glaucoma medications. Eur J Ophthalmol 2007; 17: 341–349.

50.

Schuman

. Antiglaucoma medications: a review of safety and tolerability issues related to their use. Clin Ther 2000; 22: 167–208.

51.

Stewart

Nelson

. Ocular surface disease in patients with ocular hypertension and glaucoma. Curr Eye Res 2011; 36: 391–398.

52.

Serle

Toor

Fahim

, et al. The effect of varying dosing interval on the efficacy of intraocular pressure lowering drugs. Invest Ophthalmol Vis Sci 2004; 45: 971. https://iovs.arvojournals.org/article.aspx?articleid=2406778 (2004) .

53.

Wolfram

Stahlberg

Pfeiffer

. Patient-Reported nonadherence with glaucoma therapy. J Ocul Pharmacol Therape Offic J Assoc Ocul Pharmacol Therape 2019; 35: 223–228.

54.

Almidani

Pan

Bradley

, et al. The effect of medication adherence on intraocular pressure and glaucoma progression. Ophthalmology Glaucoma 2025; 9: 158–165.

55.

Cordeiro Sousa

Leal

Nascimento

, et al. Use of ocular hypotensive medications in Portugal: PEM study: a cross-sectional nationwide analysis. J Glaucoma 2017; 26: 571–576.

56.

Pimenta

Sousa

Leal

, et al. Prescription pattern of ocular hypotensive drugs in Portugal and its comparison with the European guidelines - PEM study. Acta Ophthalmol 2019; 97: e1030–e1031.

57.

Bagnis

Papadia

Scotto

, et al. Antiglaucoma drugs: the role of preservative-free formulations. Saudi J Ophthalmol 2011; 25: 389–394.

58.

Fechtner

Realini

. Fixed combinations of topical glaucoma medications. Curr Opin Ophthalmol 2004; 15: 132–135.

59.

Higginbotham

. Considerations in glaucoma therapy: fixed combinations versus their component medications. Clin Ophthalmol 2010; 4: 1–9.

60.

Khouri

Realini

Fechtner

. Use of fixed-dose combination drugs for the treatment of glaucoma. Drugs Aging 2007; 24: 1007–1016.

61.

Gordon

Beiser

Brandt

, et al. The ocular hypertension treatment study: baseline factors that predict the onset of primary open-angle glaucoma. Archives Ophthalmol (Chicago, Ill. 1960) 2002; 120: 714–720. discussion 829-30.

62.

Heijl

Leske

Bengtsson

, et al. Reduction of intraocular pressure and glaucoma progression: results from the early manifest glaucoma trial. Archives Ophthalmol (Chicago, Ill. 1960) 2002; 120: 1268–1279.

63.

Lichter

Musch

Gillespie

, et al. Interim clinical outcomes in the collaborative initial glaucoma treatment study comparing initial treatment randomized to medications or surgery. Ophthalmology 2001; 108: 1943–1953.

64.

Sultan

Mansberger

Lee

. Understanding the importance of IOP variables in glaucoma: a systematic review. Surv Ophthalmol 2009; 54: 643–662.

65.

Leske

Heijl

Hussein

, et al. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Archives Ophthalmol (Chicago, Ill. 1960) 2003; 121: 48–56.

66.

Kolko

Faergemann Hansen

Dal L

, et al. Predictors and long-term patterns of medication adherence to glaucoma treatment in Denmark-an observational registry study of 30 100 Danish patients with glaucoma. BMJ Open Ophthalmol 2024; 9: e001607. doi: 10.1136/bmjophth-2023-001607

67.

Stalmans

Sunaric Mégevand

Cordeiro

, et al. Preservative-free treatment in glaucoma: who, when, and why. Eur J Ophthalmol 2013; 23: 518–525.

68.

Misiuk-Hojlo

Pomorska

Mulak

, et al. The RELIEF study: tolerability and efficacy of preservative-free latanoprost in the treatment of glaucoma or ocular hypertension. Eur J Ophthalmol 2019; 29: 210–215.

69.

Harasymowycz

Hutnik

Rouland

J-F

, et al. Preserved versus preservative-free latanoprost for the treatment of glaucoma and ocular hypertension: a post hoc pooled analysis. Adv Ther 2021; 38: 3019–3031.

70.

Theodosiadis

Konstas

Halkiadakis

, et al. Preservative-free versus preserved latanoprost eye drops for reducing intraocular pressure: a non-inferiority phase iii randomized, multi-center, single-blind, parallel-group controlled trial. Med Hypothesis, Discov, Innov Ophthalmol 2020; 9: 273–283.

71.

Day

Walters

Schwartz

, et al. Bimatoprost 0.03% preservative-free ophthalmic solution versus bimatoprost 0.03% ophthalmic solution (lumigan) for glaucoma or ocular hypertension: a 12-week, randomised, double-masked trial. Br J Ophthalmol 2013; 97: 989–993.

72.

Erb

Topouzis

Jayaram

, et al. Preclinical and clinical pharmacokinetics of a new preservative-free bimatoprost 0.01% ophthalmic gel to treat glaucoma and ocular hypertension. J Ocul Pharmacol Therapeu Off J Assoc Ocul Pharmacol Therapeu 2025; 41: 8–16.

73.

Muñoz-Negrete

Topouzis

Oddone

, et al. Preservative-Free bimatoprost 0.01% ophthalmic gel for glaucoma therapy: a phase III randomized controlled trial. J Glaucoma 2024; 33: 422–430.

74.

Gross

Peace

Smith

, et al. Duration of IOP reduction with travoprost BAK-free solution. J Glaucoma 2008; 17: 217–222.

75.

Ranno

Sacchi

Brancato

, et al. A prospective study evaluating IOP changes after switching from a therapy with prostaglandin eye drops containing preservatives to nonpreserved tafluprost in glaucoma patients. Sci World J 2012; 2012: 804730.

76.

Uusitalo

Chen

Pfeiffer

, et al. Switching from a preserved to a preservative-free prostaglandin preparation in topical glaucoma medication. Acta Ophthalmol (Copenh) 2010; 88: 329–336.

77.

Guldhammer Skov

Santaolalla Rives

Freiberg

, et al. Comparative efficacy and safety of preserved versus preservative-free beta-blockers in patients with glaucoma or ocular hypertension: a systematic review. Acta Ophthalmol (Copenh) 2022; 100: 253–261.

78.

Frezzotti

Fogagnolo

Haka

, et al. In vivo confocal microscopy of conjunctiva in preservative-free timolol 0.1% gel formulation therapy for glaucoma. Acta Ophthalmol (Copenh) 2014; 92: e133–e140.

79.

Cucherat

Stalmans

Rouland

. Relative efficacy and safety of preservative-free latanoprost (T2345) for the treatment of open-angle glaucoma and ocular hypertension: an adjusted indirect comparison meta-analysis of randomized clinical trials. J Glaucoma 2014; 23: e69–e75.

80.

Wang

Zhang

Chi

, et al. A novel fixed-combination timolol-netarsudil-latanoprost ophthalmic solution for the treatment of glaucoma and ocular hypertension. Asian J Pharm Sci 2022; 17: 938–948.

81.

Rouland

J-F

Traverso

Stalmans

, et al. Efficacy and safety of preservative-free latanoprost eyedrops, compared with BAK-preserved latanoprost in patients with ocular hypertension or glaucoma. Br J Ophthalmol 2013; 97: 196–200.

82.

Hommer

Schmidl

Kromus

, et al. Effect of changing from preserved prostaglandins to preservative-free tafluprost in patients with glaucoma on tear film thickness. Eur J Ophthalmol 2018; 28: 385–392.

83.

Ruangvaravate

Choojun

Srikulsasitorn

, et al. Ocular surface changes after switching from other prostaglandins to tafluprost and preservative-free tafluprost in glaucoma patients. Clin Ophthalmol (Auckland, N.Z.) 2020; 14: 3109–3119.

84.

Walimbe

Chelerkar

Bhagat

, et al. Effect of benzalkonium chloride-free latanoprost ophthalmic solution on ocular surface in patients with glaucoma. Clin Ophthalmol (Auckland, N.Z.) 2016; 10: 821–827. https://www.embase.com/search/results?subaction=viewrecord&id=L610312716&from=export (2016) .

85.

Suzuki

Teranishi

Sagara

, et al. Safety and Efficacy of Benzalkonium Chloride-optimized Tafluprost in Japanese Glaucoma Patients with Existing Superficial Punctate Keratitis. J Glaucoma 2015; 24: e145–e150.

86.

Bonnin

Nezzar

Dubray

, et al. Plasma levels and systemic safety of 0.1% unpreserved timolol maleate gel, 0.5% timolol aqueous solution and 0.5% timolol maleate gel. J Fr Ophtalmol 2012; 35: 9–16.

87.

Metheetrairut

Leumsamran

Rojananin

, et al. A comparison of 0.1% timolol eye gel and 0.5% timolol eye drop in patients with chronic angle-closure glaucoma. J Med Assoc Thai 2012; 95: S116–S122.

88.

Mayer

von der Ohe

. Efficacy of a novel hydrogel formulation in human volunteers. Ophthalmologica. Journal International D’ophtalmologie. International Journal of Ophthalmology. Zeitschrift fur Augenheilkunde 1996; 210: 101–103.

89.

Rolle

Curto

Alovisi

, et al. Timogel® vs timolol 0.5% ophthalmic solution: efficacy, safety, and acceptance. Eur J Ophthalmol 2012; 22: 28–33.

90.

Uusitalo

Niño

Tahvanainen

, et al. Efficacy and systemic side-effects of topical 0.5% timolol aqueous solution and 0.1% timolol hydrogel. Acta Ophthalmol Scand 2005; 83: 723–728.

91.

Volotinen

Mäenpää

Kautiainen

, et al. Ophthalmic timolol in a hydrogel vehicle leads to minor inter-individual variation in timolol concentration in aqueous humor. Eur J Pharm Sci 2009; 36: 292–296.

92.

Niño

Tahvanainen

Uusitalo

, et al. Cardiovascular effects of ophthalmic 0.5% timolol aqueous solution and 0.1% timolol hydrogel. Clin Physiol Funct Imaging 2002; 22: 271–278.

93.

Deshpande

Sonty

Ahmad

. Evaluating intraocular pressure-lowering solutions for the treatment of open-angle glaucoma: comparison between bimatoprost 0.03% and bimatoprost 0.01% - an observational switch study. Clin Ophthalmol (Auckland, N.Z.) 2017; 11: 1371–1376.

94.

Figus

Nardi

Piaggi

, et al. Bimatoprost 0.01% vs bimatoprost 0.03%: a 12-month prospective trial of clinical and in vivo confocal microscopy in glaucoma patients. Eye (Lond) 2014; 28: 422–429.

95.

Katz

Cohen

Batoosingh

, et al. Twelve-month, randomized, controlled trial of bimatoprost 0.01%, 0.0125%, and 0.03% in patients with glaucoma or ocular hypertension. Am J Ophthalmol 2010; 149: 661–671.e1.

96.

Kook

Simonyi

Sohn

, et al. Bimatoprost 0.01% for previously treated patients with open-angle glaucoma or ocular hypertension in the Korean clinical setting. Jpn J Ophthalmol 2015; 59: 325–334.

97.

Myers

Vold

Zaman

, et al. Bimatoprost 0.01% or 0.03% in patients with glaucoma or ocular hypertension previously treated with latanoprost: two randomized 12-week trials. Clin Ophthalmol (Auckland, N.Z.) 2014; 8: 643–652.

98.

Petricca

Celenza

Costagliola

, et al. Cytotoxicity, mitochondrial functionality, and redox status of human conjunctival cells after short and chronic exposure to preservative-free bimatoprost 0.03% and 0.01%: an in vitro comparative study. Int J Mol Sci 2022; 23: 14113. doi: 10.3390/ijms232214113

99.

Konstas

Holló

Boboridis

. Preservative-free gel-formulated glaucoma therapies: learning from the past, looking to the future. Adv Ther 2025; 42: 5896–5930. doi: 10.1007/s12325-025-03342-0

100.

Stewart

Day

, et al. Efficacy and safety of timolol maleate/latanoprost fixed combination versus timolol maleate and brimonidine given twice daily. Acta Ophthalmol Scand 2003; 81: 242–246.

101.

Mrukwa-Kominek

Misiuk-Hojlo

Csutak

, et al. A randomized clinical trial comparing three fixed combinations of bimatoprost with timolol in patients with open-angle glaucoma or ocular hypertension. Curr Med Res Opin 2023; 39: 775–783.

102.

Cordeiro

Oddone

Mermeklieva

, et al. Low-concentration bimatoprost 0.01% and timolol 0.1% eye gel versus bimatoprost 0.03% and timolol 0.5% eye drops in open-angle glaucoma or ocular hypertension: a phase III randomised study. Br J Ophthalmol 2025; 110: 403–409.

103.

Hollo

Ropo

. Intraocular pressure decrease with preservative-free fixed and unfixed combination of tafluprost and timolol in pseudoexfoliative glaucoma. Curr Med Res Opin 2015; 31: 13–16.

104.

Lazreg

Assaf

Abdelrahman

, et al. Efficacy and safety of preservative-free anti-glaucomatous eye drops (dorzolamide/timolol) in ocular hypertension and/or glaucoma. Int Ophthalmol 2025; 45: 30. doi: 10.1007/s10792-025-03411-x

105.

Oddone

Tanga

Giammaria

, et al. 24-Hour Evaluation of the effectiveness and tolerability of preservative-free tafluprost-timolol fixed combination in open-angle glaucoma or ocular hypertensive patients previously treated with preserved latanoprost. Clin Ophthalmol (Auckland, N.Z.) 2024; 18: 1751–1760.

106.

Spaeth

Bernstein

Caprioli

, et al. Control of intraocular pressure and fluctuation with fixed-combination brimonidine-timolol versus brimonidine or timolol monotherapy. Am J Ophthalmol 2011; 151: 93–99.e4.

107.

Brandt

Cantor

Katz

, et al. 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 2008; 17: 211–216.

108.

Hommer

. A double-masked, randomized, parallel comparison of a fixed combination of bimatoprost 0.03%/timolol 0.5% with non-fixed combination use in patients with glaucoma or ocular hypertension. Eur J Ophthalmol 2007; 17: 53–62.

109.

Russ

Nogueira-Filho

Barros

, et al. Ocular surface evaluation in patients treated with a fixed combination of prostaglandin analogues with 0.5% timolol maleate topical monotherapy: a randomized clinical trial. Clinics (Sao Paulo, Brazil) 2013; 68: 1318–1324.

110.

Konstas

Labbé

Katsanos

, et al. The treatment of glaucoma using topical preservative-free agents: an evaluation of safety and tolerability. Expert Opin Drug Saf 2021; 20: 453–466.

111.

Campbell

Schwartz

Labounty

, et al. Comparison of adherence and persistence with bimatoprost 0.01% versus bimatoprost 0.03% topical ophthalmic solutions. Curr Med Res Opin 2013; 29: 1201–1209.

112.

Barber

Strahlman

Laibovitz

, et al. Validation of a questionnaire for comparing the tolerability of ophthalmic medications. Ophthalmology 1997; 104: 334–342.

113.

Quaranta

Katsanos

Floriani

, et al. Circadian intraocular pressure and blood pressure reduction with timolol 0.5% solution and timogel 0.1% in patients with primary open-angle glaucoma. J Clin Pharmacol 2012; 52: 1552–1557.

114.

Pfennigsdorf

Eschstruth

Häsemeyer

, et al. Preservative-free bimatoprost 0.03%/timolol 0.5% fixed combination in patients with glaucoma in clinical practice. Clin Ophthalmol (Auckland, N.Z.) 2016; 10: 1837–1846.

115.

Solish

DeLucca

Cassel

, et al. Dorzolamide/Timolol fixed combination versus concomitant administration of brimonidine and timolol in patients with elevated intraocular pressure: a 3-month comparison of efficacy, tolerability, and patient-reported measures. J Glaucoma 2004; 13: 149–157.

116.

Bacharach

Delgado

Iwach

. Comparison of the efficacy of the fixed-combination timolol/dorzolamide versus concomitant administration of timolol and dorzolamide. J Ocul Pharmacol Ther 2003; 19: 93–96.

117.

Gandolfi

Paredes

Goldberg

, et al. Comparison of a travoprost BAK-free formulation preserved with polyquaternium-1 with BAK-preserved travoprost in ocular hypertension or open-angle glaucoma. Eur J Ophthalmol 2012; 22: 34–44.

118.

Gandolfi

Lim

Sanseau

, et al. Randomized trial of brinzolamide/brimonidine versus brinzolamide plus brimonidine for open-angle glaucoma or ocular hypertension. Adv Ther 2014; 31: 1213–1227.

119.

Higginbotham

Diestelhorst

Pfeiffer

, et al. The efficacy and safety of unfixed and fixed combinations of latanoprost and other antiglaucoma medications. Surv Ophthalmol 2002; 47: S133–S140.

120.

Hollo

Hommer

Anton

, et al. Efficacy, safety, and tolerability of preservative-free fixed combination of tafluprost 0.0015%/Timolol 0.5% versus concomitant use of the ingredients. J Ocul Pharmacol Ther 2014; 30: 468–475.

121.

Barnebey

Robin

. Adherence to fixed-combination versus unfixed travoprost 0.004%/timolol 0.5% for glaucoma or ocular hypertension: a randomized trial. Am J Ophthalmol 2017; 176: 61–69.

122.

Diestelhorst

Larsson

L-I

. A 12 week study comparing the fixed combination of latanoprost and timolol with the concomitant use of the individual components in patients with open angle glaucoma and ocular hypertension. Br J Ophthalmol 2004; 88: 199–203.

123.

Hasebe

Kashiwagi

Tsumura

, et al. Changes in adherence and associated factors among patients on newly introduced prostaglandin analog and timolol fixed-combination therapy. Patient Prefer Adherence 2018; 12: 1567–1577.

124.

Shirai

Matsuoka

Nakazawa

. Comparison of adherence between fixed and unfixed topical combination glaucoma therapies using Japanese healthcare/pharmacy claims database: a retrospective non-interventional cohort study. BMC Ophthalmol 2021; 21: 52.

125.

Toumanidou

Diafas

Georgiadis

, et al. Fixed versus unfixed combination of topical latanoprost/timolol for glaucoma: an observational study investigating the level of adherence and ocular surface health. J Clin Med 2023; 12: 3137. doi: 10.3390/jcm12093137

126.

Bron

Baudouin

Denis

, et al. Satisfaction and compliance of ocular hypertensive and glaucoma patients topically treated with a combination therapy. Journal Francais D’ophtalmologie 2008; 31: 659–665.

127.

Gugleta

Orgül

Flammer

. Experience with Cosopt, the fixed combination of timolol and dorzolamide, after switch from free combination of timolol and dorzolamide, in Swiss ophthalmologists’ offices. Curr Med Res Opin 2003; 19: 330–335.

128.

Herceg

Noecker

. Travoprost/timolol fixed combination. Expert Opin Pharmacother 2008; 9: 1059–1065.

129.

Inoue

Okayama

Higa

, et al. Ocular hypotensive effects and safety over 3 months of switching from an unfixed combination to latanoprost 0.005%/timolol maleate 0.5% fixed combination. J Ocul Pharmacol Ther 2011; 27: 581–587.

130.

Inoue

Shiokawa

Sugahara

, et al. Three-month eavaluation of dorzolamide hydrochloride/timolol maleate fixed-combination eye drops versus the separate use of both drugs. Jpn J Ophthalmol 2012; 56: 559–563.

131.

Inoue

Kawashima

Katakura

, et al. Switching from concomitant therapy to tafluprost/timolol fixed combination. Clinical Ophthalmology (Auckland, N.Z.) 2018; 12: 549–554.

132.

Stewart

Kruft

Nelson

, et al. Ophthalmologist attitudes regarding fixed combination treatment for glaucoma in the European union. Eur J Ophthalmol 2009; 19: 588–593.

133.

Garcia-Medina

Benitez-Del-Castillo

Rodríguez-Agirretxe

, et al. Treatment of open-angle glaucoma and ocular hypertension with preservative-free tafluprost/timolol fixed-dose combination therapy: results from the VISIONARY study population in Spain. J Ocul Pharmacol Ther 2022; 38: 252–260.

134.

Oddone

Tanga

Kóthy

, et al. Treatment of open-angle glaucoma and ocular hypertension with preservative-free tafluprost/timolol fixed-dose combination therapy: the VISIONARY study. Adv Ther 2020; 37: 1436–1451.

135.

Kitazawa

Smith

Sasaki

, et al. Travoprost 0.004%/timolol 0.5%-fixed combination with and without benzalkonium chloride: a prospective, randomized, doubled-masked comparison of safety and efficacy. Eye (Lond) 2011; 25: 1161–1169.

136.

Roman

. PASSY “Patient satisfaction survey” in glaucoma disease: Spanish results. Invest Ophthalmol Visual Sci 2015; 56: 5022. https://www.embase.com/search/results?subaction=viewrecord&id=L615920783&from=export (2015) .

137.

Sun

Lin

Duan

, et al. Patient satisfaction with fixed-combination bimatoprost/timolol ophthalmic solution: a survey study in patients with glaucoma in China. Patient Prefer Adherence 2017; 11: 845–852.

138.

Pinto L

Vandewalle

Gerlier

, et al. Improvement in glaucoma patient quality of life by therapy switch to preservative-free timolol/dorzolamide fixed combination. Ophthalmologica. Journal International D’ophtalmologie. International Journal of Ophthalmology. Zeitschrift fur Augenheilkunde 2014; 231: 166–171.

139.

Kumar

Singh

Ichhpujani

, et al. Correlation of ocular surface disease and quality of life in Indian glaucoma patients: BAC-preserved versus BAC-free travoprost. Turkish J Ophthalmol 2020; 50: 75–81.

140.

Lemij

Stalmans

Erb

, et al. Patient satisfaction related to tolerance when treated with preservative-free latanoprost; results from the PASSY survey in six European countries. Invest Ophthalmol Visual Sci 2016; 57: 3026. https://www.embase.com/search/results?subaction=viewrecord&id=L616082259&from=export (2016) .

141.

Muñoz Negrete

Lemij

Erb

. Switching to preservative-free latanoprost: impact on tolerability and patient satisfaction. Clin Ophthalmol (Auckland, N.Z.) 2017; 11: 557–566.

142.

Skalicky

Goldberg

McCluskey

. Ocular surface disease and quality of life in patients with glaucoma. Am J Ophthalmol 2012; 153: 1–9.e2.

143.

Scelfo

ElSheikh

Shamim

, et al. Ocular surface disease in glaucoma patients. Curr Eye Res 2023; 48: 219–230.

144.

Boso AL

Gasperi

Fernandes

, et al. Impact of ocular surface disease treatment in patients with glaucoma. Clin Ophthalmol (Auckland, N.Z.) 2020; 14: 103–111.

145.

Garcia-Feijoo

Sampaolesi

. A multicenter evaluation of ocular surface disease prevalence in patients with glaucoma. Clin Ophthalmol 2012; 6: 441–446.

146.

Yıldırım

Bozkurt

Yüksel

, et al. Prevalence of ocular surface disease and associated risk factors in glaucoma patients: a survey study of ophthalmologists. Turkish J Ophthalmol 2022; 52: 302–308.

147.

Nieminen

Uusitalo

Turjanmaa

, et al. Association between low plasma levels of ophthalmic timolol and haemodynamics in glaucoma patients. Eur J Clin Pharmacol 2005; 61: 369–374.

148.

K-H

Yoo

Park

J-H

, et al. Eye drop dispenser type and medication possession ratio in patients with glaucoma: single-use containers versus multiple-use bottles. Am J Ophthalmol 2018; 188: 9–18.

149.

Higginbotham

Hansen

Davis

, et al. Glaucoma medication persistence with a fixed combination versus multiple bottles. Curr Med Res Opin 2009; 25: 2543–2547.

150.

Barber

Hartmann

. Benzalkonium chloride: a systematic review of its environmental entry through wastewater treatment, potential impact, and mitigation strategies. Crit Rev Environ Sci Technol 2022; 52: 2691–2719.

151.

d'Aranda

Pons

Chelly

, et al. Discarded intravenous medication in the ICU: the GAME-OVER multicenter prospective observational study. Crit Care 2025; 29: 84.

152.

Davies

McAlister

Eckelman

, et al. Environmental and financial impacts of perioperative paracetamol use: a multicentre international life-cycle assessment. Br J Anaesth 2024; 133: 1439–1448.

153.

Mankes

. Propofol wastage in anesthesia. Anesth Analg 2012; 114: 1091–1092.

154.

Kholdebarin

Campbell

Jin

Y-P

, et al. Multicenter study of compliance and drop administration in glaucoma. Can J Ophthalmol 2008; 43: 454–461.

155.

Klatte

Schaefer

H-C

Hempel

. Pharmaceuticals in the environment – A short review on options to minimize the exposure of humans, animals and ecosystems. Sustain Chem Pharmacy 2017; 5: 61–66.

156.

Hommer

Thygesen

Ferreras

, et al. A European perspective on costs and cost effectiveness of ophthalmic combinations in the treatment of open-angle glaucoma. Eur J Ophthalmol 2008; 18: 778–786.

157.

Foo

March

Elferink

, et al. The carbon footprint of glaucoma care with drops or laser first. Clin Exp Ophthalmol 2025; 53: 435–437. doi: 10.1111/ceo.14491

158.

Ventura

Saheb

Solari

, et al. Cost considerations of the new fixed combinations for glaucoma medical therapy. J Clin Pharm Ther 2005; 30: 251–254.

159.

Curran

Orman

. Bimatoprost/timolol: a review of its use in glaucoma and ocular hypertension. Drugs and Aging 2009; 26: 169–184.

160.

Barayev

Geffen

Nahum

, et al. Changes in prices and eye-care providers prescribing patterns of glaucoma medications in the United States between 2013 and 2019. J Glaucoma 2021; 30: e83–e89.

161.

Wong

Patel

Kowalski

, et al. An adherence based cost-consequence model comparing bimatoprost 0.01% to bimatoprost 0.03%. Curr Med Res Opin 2013; 29: 1191–1200.

162.

Hogg

Connor

. 10-year Trends in English primary care glaucoma prescribing. Eye (London, England) 2020; 34: 192–196.

163.

Wickstrøm

Centofanti

Johnson

. Costs and effects of fixed combination therapies in open angle glaucoma. Value Health 2010; 13: A399–A400.

164.

Steven

Alaghband

Lim

. Preservatives in glaucoma medication. Br J Ophthalmol 2018; 102: 1497–1503.

165.

Tabet

Stewart

Feldman

, et al. A review of additivity to prostaglandin analogs: fixed and unfixed combinations. Surv Ophthalmol 2008; 53: S85–S92.

166.

Gazzard

Konstantakopoulou

Garway-Heath

, et al. Laser in glaucoma and ocular hypertension (LiGHT) trial. A multicentre, randomised controlled trial: design and methodology. Br J Ophthalmol 2018; 102: 593–598.

167.

McAlinden

. Selective laser trabeculoplasty (SLT) vs other treatment modalities for glaucoma: systematic review. Eye (Lond) 2014; 28: 249–258.

168.

Gulati

Aref

. Oral Acetazolamide for intraocular pressure lowering: balancing efficacy and safety in ophthalmic practice. Expert Rev Clin Pharmacol 2021; 14: 955–961.

169.

Kolko

Gazzard

Baudouin

, et al. Impact of glaucoma medications on the ocular surface and how ocular surface disease can influence glaucoma treatment. Ocul Surf 2023; 29: 456–468.

170.

Lan

C-H

Chiu

T-H

Yen

W-T

, et al. Artificial intelligence in glaucoma: advances in diagnosis, progression forecasting, and surgical outcome prediction. Int J Mol Sci 2025; 26: 4473.