What are the adverse effects of Long-Acting Muscarinic Antagonist (LAMA) and Long-Acting Beta-Agonist (LABA)?

From the Guidelines

The combination of LAMA and LABA can cause several adverse effects, including dry mouth, constipation, urinary retention, blurred vision, headaches, nasopharyngitis, tremors, palpitations, tachycardia, and increased blood glucose levels, as reported in recent studies 1. When used together, LAMAs and LABAs can have a synergistic effect on the respiratory system, but this combination also increases the risk of adverse effects.

• LAMAs commonly cause anticholinergic side effects such as dry mouth, constipation, and urinary retention, as well as headaches and nasopharyngitis 1.
• LABAs can cause tremors, palpitations, tachycardia, and headaches due to beta-receptor stimulation, and may also lead to hypokalemia and increased blood glucose levels 1. The most recent study 1 highlights the importance of considering the risk-benefit ratio when using LAMA and LABA combination therapy, particularly in patients with severe COPD, as the incidence of pneumonia is higher with inhaled ICS-containing maintenance therapy. The risk of pneumonia is a significant concern, with a number needed to harm of 33 patients for 1 year to cause one pneumonia, as reported in the 2023 Canadian Thoracic Society guideline 1. It is essential to weigh the benefits of LAMA and LABA combination therapy against the potential risks and to monitor patients closely for adverse effects, as the benefits of reduced exacerbations and improved lung function may outweigh the risks for some patients 1.

From the FDA Drug Label

Use of LABA may result in the following: • Serious asthma-related events – hospitalizations, intubations, death [see Warnings and Precautions (5.1)] • Cardiovascular and central nervous system effects [see Warnings and Precautions (5.12)]

Use of a LABA, including STIOLTO RESPIMAT, without an inhaled corticosteroid is contraindicated in patients with asthma [see Warnings and Precautions (5. 1)].

The increased risk of asthma-related death is considered a class effect of LABA, including olodaterol, one of the active ingredients in STIOLTO RESPIMAT.

The adverse effects of LAMA (Long-Acting Muscarinic Antagonist) and LABA (Long-Acting Beta2-Adrenergic Agonist) include:

• Serious asthma-related events: hospitalizations, intubations, death
• Cardiovascular and central nervous system effects
• Hypersensitivity reactions: angioedema, itching, or rash
• Excessive use of STIOLTO RESPIMAT and use with other long-acting beta2-agonists may result in an overdose.

2 and 3

From the Research

Adverse Effects of LAMA and LABA

• The combination of long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) is thought to leverage different pathways to induce bronchodilation using submaximal drug doses, increasing the benefits and minimizing receptor-specific side effects 4.
• However, the use of LAMA/LABA combination therapy may be associated with an increased risk of all-cause death compared to LABA+ICS, although the absolute risk is low 5.
• LAMA/LABA combination therapy may also decrease the odds of pneumonia compared to LABA+ICS 5.
• The most common adverse effects of LAMA/LABA combination therapy are not explicitly stated in the provided studies, but it is mentioned that the combination therapy offers a simplified means of maximizing bronchodilation for COPD patients, with improvements in lung function being mirrored by benefits in terms of symptoms and exacerbations 6.

Comparison of LAMA/LABA and LABA/ICS

• The odds of having an exacerbation are similar for LAMA/LABA compared with LABA/ICS 5.
• The odds of having a serious adverse event are also similar between LAMA/LABA and LABA/ICS 5.
• LAMA/LABA combination therapy may offer a greater improvement in trough FEV1 compared to LABA/ICS 5.
• The use of LAMA/LABA combination therapy may be associated with a similar improvement in quality of life, as measured by the SGRQ, compared to LABA/ICS 5.

Clinical Evidence and Future Perspectives

• Long-term clinical trials show that LAMA/LABA combination therapy is superior to monocomponent therapy in terms of trough FEV1, although the FEV1 improvement is limited to approximately 80-90% of the added monocomponent values 6.
• LAMA/LABA combination therapy is associated with the largest mean changes in symptoms and health status that are above the minimal clinically important difference, in contrast to monocomponents 6.
• Further studies are needed to define the optimal place of LAMA/LABA combination therapy in treatment guidelines 6.