Clinicians’ perspectives on the use of triple fixed-dose combination timolol + brinzolamide + brimonidine in glaucoma management in Indian settings

INTRODUCTION

Glaucoma, a leading cause of irreversible vision loss globally, is concentrated in lowsociodemographic index regions, where access to clinical diagnosis and treatment remains a challenge.^[1,2] Findings from the Global Burden of Disease 2019 study highlight the increasing global burden of glaucoma from 1990 to 2019. The total number of glaucoma cases rose from 3,881,624 in 1990 to 7,473,400 in 2019, while DALYs increased from 442,182 to 748,308 over the same period.^[1] At present, an estimated 64.3 million individuals aged 40–80 years are affected by glaucoma worldwide, with projections indicating an increase to 76.0 million by 2020 and 111.8 million by 2040.^[3] By 2040, an additional 27.8 million individuals in Asia are expected to be affected by glaucoma, with India and China bearing the highest burden. In India, glaucoma is responsible for blindness in 1.2 million individuals, accounting for 5.5% of total blindness, making it one of the leading causes of irreversible vision loss in the country.^[4]

Fixed-dose combinations (FDCs) play a crucial role in glaucoma management by enhancing treatment efficacy through the complementary mechanisms of their active ingredients. They also improve patient adherence, reduce exposure to preservatives and associated adverse effects, and help alleviate the financial burden of multiple medications.^[5] A variety of topical intraocular pressure (IOP)-lowering medications are available, each with distinct mechanisms of action, including β-blockers, prostaglandin analogs (PGAs), carbonic anhydrase inhibitors (CAIs), α2-adrenergic agonists, and parasympathomimetic agents.^[2]

Brinzolamide, a selective carbonic anhydrase II inhibitor, lowers IOP by reducing aqueous humor production through decreased bicarbonate ion formation, thereby limiting sodium and fluid transport into the posterior chamber.^[6,7] Timolol maleate, a non-selective β-adrenergic blocker, lowers IOP by reducing aqueous humor production and possibly enhancing outflow. It also decreases blood pressure by blocking adrenergic receptors and sympathetic outflow, with uncertain mechanisms contributing to its negative chronotropic and inotropic effects.^[8] Brimonidine is an β-adrenergic receptor agonist that lowers IOP by reducing aqueous humor production and, over time, enhancing uveoscleral outflow. It acts on β-adrenergic receptors in the iris–ciliary body, effectively regulating fluid dynamics within the eye to manage glaucoma and ocular hypertension (OHT).^[9]

Although there were several studies highlighting its efficacy, there is a dearth of studies among clinicians in actual practice. This survey aims to gather expert perspectives on current trends in glaucoma management practices among Indian clinicians, with a specific focus on triple FDC therapy comprising timolol, brinzolamide, and brimonidine.

MATERIAL AND METHODS

This cross-sectional study was carried out among ophthalmologists specialized in treating glaucoma patients in the major Indian cities from June 2023 to December 2023.

RESULTS

The survey included 129 clinicians, with the majority (34.11%) reporting that newly diagnosed glaucoma cases comprise 3–5% of their total outpatient department (OPD) patient pool per month. Most clinicians (61.24%) indicated that glaucoma is most commonly detected in patients aged 50-60 years. Approximately 71% of experts reported that glaucoma is primarily detected during routine IOP checks and optic disc assessments conducted on all patients. About 32% noted that <10% of their patients are diagnosed at a late or advanced stage of glaucoma. Nearly 44% of the respondents reported detecting only 11–20% of glaucoma cases at an early stage. Around 43% indicated that fewer than 10% of their newly diagnosed glaucoma patients have an IOP within the normal range (12–21 mmHg).

Around 40% of clinicians preferred individual one-to-one sessions to educate glaucoma patients. More than half of the clinicians (54.26%) indicated that fewer than half of their patients achieve target IOP with a single drug within the first 12 weeks of treatment. In addition, 46% reported that up to half of their glaucoma patients require dual drug therapy for effective management. Majority of the experts (70.54%) observed that treatment adherence among glaucoma patients, particularly those on more than one drop, ranges between 75% and 90%. According to 57% of the clinicians, brinzolamide is the carbonic anhydrase inhibitor of choice for glaucoma management. Furthermore, around 39% stated that fewer than 10% of their existing glaucoma patients are on maximal medical therapy involving a 3–4 drug regimen.

Around 47% of clinicians reported treating fewer than five patients with the triple drug FDC timolol, brinzolamide, and brimonidine in recent months [Table 1]. A significant proportion (89.15%) highlighted multiple benefits, including decreasing aqueous humor production, improving ocular blood flow, and providing neuroprotection for the optic nerve [Figure 1]. The majority (30.23%) reported that the triple drug FDC, when used as a single drop, resulted in a 21–30% IOP reduction [Figure 2]. Most clinicians (42%) emphasized several advantages of the triple FDC, such as reducing the number of drops and preservatives instilled daily, improving compliance, preventing washout effects from multiple drops, minimizing ocular surface damage, providing cost savings, and simplifying the addition of another anti-glaucoma drug class [Table 2].

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Figure 1:

Distribution of response to the clinicians’ perspectives on the effects of the triple fixed-dose combination timolol + brinzolamide + brimonidine. FDC: Fixed dose combination.

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Figure 2:

Distribution of response on the clinicians’ perspectives about the intraocular pressure-lowering effect of the new fixed-dose combination when used as a single drop. FDC: Fixed dose combination, IOP: Intraocular pressure.

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Most clinicians (59.69%) reported being satisfied with the additional IOP reduction achieved after switching from a dual drug FDC to the triple drug [Figure 3]. More than half (53.49%) rated the tolerability of the new drug as very good, while 33.33% considered it excellent [Figure 4]. The majority (34.11%) indicated that reduced preservative exposure with timolol, brimonidine, and brinzolamide FDC eye drops decreases the risk of ocular surface damage, and 31% noted that this reduction potentially improves patient compliance [Table 3]. Most clinicians recommended the triple drug FDC eye drops for patients requiring more than three drugs to achieve target IOP, patients on PGA and dual drug fixed combinations who had not achieved target IOP and patients on PGA monotherapy requiring additional IOP lowering [Table 4].

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Figure 3:

Distribution of response to clinicians’ satisfaction with additional intraocular pressure lowering after switching from dual drug fixed-dose combination to the triple drug.

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Figure 4:

Distribution of response to clinicians’ perspectives on the tolerability of the new drug.

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The majority of the clinicians (41.86%) reported that the timolol + brimonidine + brinzolamide FDC eye drops reduce the total number of drops and preservatives instilled per day. A significant proportion of the clinicians (96.12%) stated that the twice daily (BID) dosing regimen of the new drug is convenient for patients. According to 45% of clinicians, 11– 25% of glaucoma patients have IOP levels above 22 mmHg despite dual drug therapy.

DISCUSSION

The study findings highlight the clinical utility and advantages of triple drug FDC timolol + brimonidine + brinzolamide in improving treatment outcomes, adherence, and reducing ocular surface complications in glaucoma management. Nearly 90% of the current survey respondents recognized the multiple mechanisms of action of this combination, including its effects on aqueous humor production, ocular blood flow, and neuroprotection of the optic nerve. This comprehensive understanding of the drug’s therapeutic effects suggests that clinicians appreciate its potential for addressing multiple aspects of glaucoma pathophysiology beyond simple IOP reduction.

There are several studies highlighting the clinical benefits of each component of the triple drug FDC. Kazemi et al. found that after 1 week of treatment, timolol reduced aqueous humor outflow facility in eyes with a healthy trabecular meshwork, as indicated by a normal baseline outflow facility.^[10] A clinical trial by Grunwald found that timolol-treated eyes showed a 12.0% increase in average red blood cell velocity (P < 0.005) and an 8.4% increase in volumetric blood flow rate (P < 0.05) compared to baseline, while no significant changes were observed in the placebo group.^[11] WoldeMussie et al. found that brimonidine reduced retinal ganglion cell death by up to 50%, while timolol showed no neuroprotective effect.^[12] Larsson found that brimonidine reduced aqueous humor flow by 33.1%, timolol by 49.9%, and their combination by 58.9%, demonstrating an additive effect.^[13] Ingram and Brubaker found that brinzolamide reduced daytime aqueous flow by 0.47 μL/min and nighttime aqueous flow by 0.16 μL/min.^[14] In healthy volunteers, topical brinzolamide treatment accelerated retinal arteriovenous passage without affecting retinal vessel diameters or retrobulbar hemodynamics. Similarly, an animal study found that brinzolamide increased optic nerve head blood flow in rabbits.^[15]

The clinical effectiveness of the triple FDC was demonstrated by the marked IOP reduction, with the majority of clinicians observing a 21–30% decrease in IOP. This substantial IOP-lowering effect is complemented by high satisfaction rates among clinicians who switched patients from dual drug combinations, with most reporting satisfactory additional IOP reduction. The multiple benefits reported by clinicians, including reduced drop burden, and improved compliance suggest that this combination could address several common challenges in glaucoma management. The safety and tolerability profile of the triple FDC is favorable, with most current survey clinicians rating it as either “very good” or “excellent.”

At present, there are limited studies on the FDC that include timolol, brimonidine, and brinzolamide in a single formulation. Lerner et al. found that the adjunctive use of brinzolamide 1%/brimonidine 0.2% FDC (BBFC) with once-daily travoprost 0.004%/timolol 0.5% FDC (TTFC) led to a clinically meaningful and statistically significant reduction in mean diurnal IOP in patients with open-angle glaucoma (OAG) or OHT. The adverse events associated with BBFC + TTFC were consistent with the known safety profiles of the individual components.^[16]

In the present study, most of the clinicians suggest that reducing preservative exposure with timolol + brimonidine + brinzolamide FDC offers several potential benefits, with the most frequently recognized being a reduced risk of ocular surface damage and improved patient compliance, which is crucial for successful glaucoma management. Most of the clinicians listed patient types that could benefit from the intervention, suggesting that the need for effective IOP management spans various clinical scenarios. These include patients requiring more than three drugs to achieve target IOP, those on a PGA and a dual-drug fixed combination but still not achieving target IOP, patients needing further IOP reduction after PGA monotherapy, and those already on a dual-drug fixed combination and PGA. This broad applicability suggests that clinicians see this triple FDC as a versatile treatment option.

Although studies on triple drug FDCs are rare, there is substantial literature validating the therapeutic benefits of various two-drug FDCs involving timolol, brinzolamide, and brimonidine. For instance, Agarwal et al.^[17] reported that the mean reduction in morning IOP was significantly greater in patients treated with the brinzolamide 1%/timolol 0.5% FDC compared to those receiving the dorzolamide 2%/timolol 0.5% FDC. In addition, 83.33% of patients in the brinzolamide/timolol group experienced perfect ocular comfort with no ocular side effects, compared to 56.67% in the dorzolamide/timolol group.^[17] Mishra et al. demonstrated that both the brinzolamide 1%/timolol 0.5% FDC and the BBFC led to a significant reduction in IOP, accompanied by a notable increase in central corneal thickness.^[18] Azmi et al. found that both the FDC of 1% brinzolamide and 0.5% timolol was associated with a lower incidence of adverse events compared to free-equivalent combination.^[19]

Davawala et al. reported that the FDC of brimonidine and timolol led to a faster and greater reduction in IOP compared to monotherapy, with no serious side effects observed.^[20] A randomized controlled trial by Reis et al. found that in patients with OAG or OHT whose IOP was inadequately controlled with travoprost 0.004% monotherapy, both brinzolamide 1% and timolol maleate 0.5% achieved significantly greater IOP reduction than brimonidine 0.2% when used as non-fixed adjuncts, with treatment being well tolerated.^[21]

The use of multiple eye drops for a chronic and often asymptomatic condition can lead to poor adherence and reduced persistence, ultimately diminishing the effectiveness of treatment. A proven strategy to enhance adherence and persistence with glaucoma medications is the use of fixed-combination formulations. The triple-drug formulation into a single solution, reducing the number of bottles needed, lowering costs, and simplifying the dosing regimen – factors that collectively improve long-term treatment adherence.^[2]

The current survey holds significant relevance, considering the limited literature available on this triple FDC therapy. A key strength of this survey is the use of a carefully designed and validated questionnaire to collect expert data, providing valuable real-world insights from practicing clinicians. It sheds light on current glaucoma management patterns in India, documents treatment preferences and decision-making processes, and highlights the challenges in glaucoma detection and management. However, the survey relies on clinician perceptions rather than objective measurements, which may introduce bias. Future research should focus on long-term efficacy and safety, direct comparisons with other treatment regimens, and patient-reported outcomes to provide a more comprehensive understanding of glaucoma management.

CONCLUSION

The current survey has highlighted the potential of the triple-drug FDC of timolol, brinzolamide, and brimonidine in glaucoma management, as evidenced by clinician recognition of its multiple therapeutic mechanisms and effectiveness in reducing IOP. This combination offers practical advantages, including reduced preservative exposure, improved patient compliance, and a favorable safety profile. It is particularly valuable for patients requiring multiple medications or those not achieving target IOP with current treatments.