Innovations in asthma therapy: is there a role for inhaled statins?

Abstract

Introduction Asthma manifests as chronic airflow obstruction with persistent inflammation and airway hyperresponsiveness. The immunomodulatory and anti-inflammatory properties of the HMG-CoA reductase (HMGCR) inhibitors (a.k.a. statins), suggest a therapeutic role in chronic inflammatory lung diseases. However, despite positive laboratory investigations and promising epidemiological data, clinical trials using statins for the treatment of asthma have yielded conflicting results. Inadequate statin levels in the airway compartment could explain these findings. Areas covered HMGCR is in the mevalonate (MA) pathway and MA signaling is fundamental to lung biology and asthma. This article will discuss clinical trials of oral statins in asthma, review lab investigations relevant to the systemic versus inhaled administration of statins, address the advantages and disadvantages of inhaled statins, and answer the question: is there a role for inhaled statins in the treatment of asthma? Expert commentary If ongoing investigations show that oral administration of statins has no clear clinical benefits, then repurposing statins for delivery via inhalation is a logical next step. Inhalation of statins bypasses first-pass metabolism by the liver, and therefore, allows for delivery of significantly lower doses to the airways at greater potency. Statins could become the next major class of novel inhalers for the treatment of asthma.

Rosuvastatin blocks allergic airway vagal hypertonia via reversed central CD73 downregulation in rats

“…In terms of the alleviating effects of statins on asthma symptoms and asthmatic decrease of pulmonary function, our results do not support the assumption that inhaled statins might have more advantage over those ingested or injected (10), since these effects might involve a direct central drug action that is independent of the deposition of inhaled drugs in the lungs.…”

“…However, some small randomized clinical trials using oral statins have yielded contradictory results. While a consistent anti-inflammatory effect of statins is validated, improved clinical outcomes in terms of symptoms or pulmonary function are not demonstrated [for review, see (10)]. The results from this study suggest that in OVA-sensitized rats, the rosuvastatin-induced improvement of pulmonary function is closely related to the reversed increase of airway vagal activity.…”

“…Both preclinical studies in animal models and some randomized clinical trials have implicated that statins also act as modulators of immune cells and are able to alleviate asthma and chronic obstructive pulmonary diseases (COPD) [for review, see (9)(10)(11)(12)(13)]. In particular, inhaled statins are thought to be more prospective in asthma treatment due to the assumed heavier drug deposition in the lungs (10). A latest retrospective clinical study even shows that in-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19 (14).…”

<p>Metabolic Dysfunction and Asthma: Current Perspectives</p>

“… 82 – 84 RCTs in severe asthma are lacking and studies using statins delivered by inhalation are also warranted. 84 Evidence of clinical benefit of metformin in asthma is also growing, 85 – 87 although it has seldom been investigated in real-life clinical settings. In particular, a decrease in asthma exacerbations in response to metformin has been reported in different populations.…”

“…Epidemiological and observational studies pointed towards therapeutic benefits in asthma, but RCTs using oral statins yielded conflicting results. [82][83][84] RCTs in severe asthma are lacking and studies using statins delivered by inhalation are also warranted. 84 Evidence of clinical benefit of metformin in asthma is also growing, [85][86][87] although it has seldom been investigated in real-life clinical settings.…”