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Introduction <p>Glaucoma is a leading cause of irreversible blindness, and many patients ultimately require escalation beyond monotherapy to maintain adequate intraocular pressure control. Although timolol-based fixed-combination therapies are widely used, real-world evidence comparing their long-term effectiveness across different drug classes remains limited. This study was conducted to compare long-term outcomes among prostaglandin analog (PGA)/timolol, carbonic anhydrase inhibitor (CAI)/timolol, and α-agonist (AA)/timolol regimens.</p> Methods <p>We emulated a hypothetical open-label pragmatic trial using Taiwan’s National Health Insurance Research Database, and included patients with incident glaucoma between 2011 and 2021 who initially received monotherapy and subsequently initiated a timolol-containing fixed-combination therapy with PGA, CAI, or AA. Propensity score-based overlap weighting was applied to balance baseline covariates, and Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The primary outcome was treatment failure, defined as the initiation of additional topical anti-glaucoma medication, incisional surgery or laser treatment, or a diagnosis of blindness. Patients were followed from fixed-combination therapy initiation until occurrence of treatment failure, death, or 31 December 2021.</p> Results <p>After weighting, the cohorts included 5714 (PGA/timolol versus CAI/timolol), 5070 (PGA/timolol versus AA/timolol), and 18,654 (AA/timolol versus CAI/timolol) patients. PGA/timolol initiation was associated with a lower rate of treatment failure compared with CAI/timolol (HR: 0.85, 95% CI 0.80–0.91) and AA/timolol (HR: 0.87, 95% CI 0.81–0.93). PGA/timolol also reduced the need for additional medications and intraocular pressure–lowering procedures compared with other regimens. CAI/timolol and AA/timolol showed no significant difference in treatment failure rates (HR: 0.97, 95% CI 0.94–1.00).</p> Conclusions <p>In a nationwide real-world setting, PGA/timolol demonstrated superior long-term effectiveness compared with both CAI/timolol and AA/timolol, resulting in lower treatment failure rates and reduced need for additional medications or procedures. These findings suggest that PGA/timolol may be associated with the most favorable long-term effectiveness among timolol-based fixed combinations.</p>

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Comparative Effectiveness of Timolol-Based Fixed-Combination Regimens for Glaucoma: a Retrospective Cohort Study Using Target Trial Emulation Framework

  • 期刊论文

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  • 发表日期：

    2026年3月16日

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  • Chin Lai,
  • Avery Shuei-He Yang,
  • Shih-Chieh Shao,
  • Lan-Hsin Chuang,
  • Chi-Chun Lai,
  • Edward Chia-Cheng Lai

摘要

Introduction

Glaucoma is a leading cause of irreversible blindness, and many patients ultimately require escalation beyond monotherapy to maintain adequate intraocular pressure control. Although timolol-based fixed-combination therapies are widely used, real-world evidence comparing their long-term effectiveness across different drug classes remains limited. This study was conducted to compare long-term outcomes among prostaglandin analog (PGA)/timolol, carbonic anhydrase inhibitor (CAI)/timolol, and α-agonist (AA)/timolol regimens.

Methods

We emulated a hypothetical open-label pragmatic trial using Taiwan’s National Health Insurance Research Database, and included patients with incident glaucoma between 2011 and 2021 who initially received monotherapy and subsequently initiated a timolol-containing fixed-combination therapy with PGA, CAI, or AA. Propensity score-based overlap weighting was applied to balance baseline covariates, and Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The primary outcome was treatment failure, defined as the initiation of additional topical anti-glaucoma medication, incisional surgery or laser treatment, or a diagnosis of blindness. Patients were followed from fixed-combination therapy initiation until occurrence of treatment failure, death, or 31 December 2021.

Results

After weighting, the cohorts included 5714 (PGA/timolol versus CAI/timolol), 5070 (PGA/timolol versus AA/timolol), and 18,654 (AA/timolol versus CAI/timolol) patients. PGA/timolol initiation was associated with a lower rate of treatment failure compared with CAI/timolol (HR: 0.85, 95% CI 0.80–0.91) and AA/timolol (HR: 0.87, 95% CI 0.81–0.93). PGA/timolol also reduced the need for additional medications and intraocular pressure–lowering procedures compared with other regimens. CAI/timolol and AA/timolol showed no significant difference in treatment failure rates (HR: 0.97, 95% CI 0.94–1.00).

Conclusions

In a nationwide real-world setting, PGA/timolol demonstrated superior long-term effectiveness compared with both CAI/timolol and AA/timolol, resulting in lower treatment failure rates and reduced need for additional medications or procedures. These findings suggest that PGA/timolol may be associated with the most favorable long-term effectiveness among timolol-based fixed combinations.