COMMENTARY

Long-Acting Muscarinic Antagonist Therapy Takes a Hit in GINA Update

Aaron B. Holley, MD

Disclosures

September 29, 2022

In keeping with the new trend for providing "living guidelines," the Global Initiative for Asthma (GINA) Scientific Committee released their latest update a few months ago. The push toward earlier initiation of inhaled corticosteroids (ICS) has dominated GINA updates since 2019, and the 2022 update is no exception. Given that we've relied on short-acting beta-agonists (SABAs) to treat mild disease for decades, this emphasis makes sense. Change doesn't happen quickly, and switching as-needed SABAs to ICS was a paradigm shift in the approach to asthma.

The 2022 GINA update also includes a few subtle differences from past editions that warrant attention. They specifically recommend against using a long-acting muscarinic antagonist (LAMA) as monotherapy. They also state that LAMA add-on to ICS/long-acting beta-agonist (LABA) therapy won't help with symptoms or quality of life. Therefore, triple therapy (ICS/LABA/LAMA) is not superior to ICS/LABA alone for treatment of dyspnea in moderate to severe asthma. So, what's with the apparent LAMA negativity?

It seems that LAMA monotherapy is simply the latest casualty of current asthma thinking. Asthma is an inflammatory disease and exacerbations are unpredictable. Medications without anti-inflammatory effects may mask severity and are associated with more exacerbations when used in isolation. Therefore, ICS is required up front, either alone or in combination with bronchodilators, to optimize safety.

The dangers of therapy without ICS first hit my radar via the Salmeterol Multicenter Research Trial (SMART) and a meta-analysis published in 2006. These papers showed that LABA monotherapy was harmful. Follow-up publications found that LABAs were safe so long as they were used in conjunction with ICS, and the US Food and Drug Administration ultimately removed the black-box warning they had applied to LABA/ICS treatment. LABA monotherapy was forever banished to the hinterlands, with scorn heaped upon those who ordered it.

SABA monotherapy was eliminated next. The GINA decision to recommend against using SABAs without ICS was driven in part by data showing that serious exacerbations can occur in patients with mild or intermittent disease. SABAs do not possess anti-inflammatory activity and may even worsen eosinophilia. Therefore, once studies demonstrated that as-needed ICS was effective, SABA monotherapy was officially retired. Those who ordered it were trolled, humiliated, and cast aside.

Now, it's LAMA's turn. Even before GINA 2022, physicians could be ostracized for ordering LAMA monotherapy, given that (1) GINA's treatment algorithms never included LAMA monotherapy as an option and (2) to my knowledge, LAMA has only been studied as monotherapy once in a major trial and was found to be inferior to ICS for mild, eosinophilic asthma and largely ineffective for noneosinophilic disease. GINA felt the need to "cancel" it as an option anyway after a large, retrospective and observational study found that LAMA monotherapy is associated with an increase in exacerbations. This makes sense, and the moral of the asthma story is that, absent meticulous phenotyping, you really need ICS on board.

What about LAMA add-on to ICS/LABA not improving symptoms or quality of life? Results from meta-analyses published in 2015 and 2018 that evaluated LAMA add-on were conflicting. One found an effect on exacerbations and the other did not. A much larger updated meta-analysis was published in 2021. The reduction in exacerbations was confirmed but the impact on asthma control and forced expiratory volume in one second was underwhelming and there was no effect on quality of life. The 2022 GINA recommendation to not use LAMA add-on for symptoms was based on these findings.

We've heard this story before. The 2020 Global Strategy for Prevention, Diagnosis, and Management of Chronic Obstructive Pulmonary Disease (GOLD) Report advocates LAMA/LABA/ICS triple therapy to reduce exacerbations and for worsening dyspnea. As with asthma though, the data for dyspnea really aren't there. GINA now acknowledges this, while GOLD sort of acknowledges it (the 2022 GOLD report advocates adding LAMA to ICS/LABA treatment for dyspnea but not ICS to LABA/LAMA treatment).

In summary, we can now add LAMA to the list of asthma mono-inhaler therapies that are off the table as a treatment for asthma. My personal feeling is that triple therapy is oversold and overused when chasing symptoms for asthma or chronic obstructive pulmonary disease. My assumption is that ease of access and the lack of nuance in the popular GOLD (A-D categorization and management) and GINA (step-up therapy) treatment algorithms contribute to this. For those who bother to dig a little deeper though, it's clear that in 2022, both GOLD and GINA are backing away from triple-therapy for symptoms.

Aaron B. Holley, MD, is an associate professor of medicine at Uniformed Services University and program director of pulmonary and critical care medicine at Walter Reed National Military Medical Center. He covers a wide range of topics in pulmonary, critical care, and sleep medicine.

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