Relationship Between Gender and the Effectiveness of Montelukast: An Italian/Danish Register-Based Retrospective Cohort Study

Abstract

Rationale: Gender-related differences in asthma prevalence, pathophysiology and clinical features induced by sex steroids have been investigated, however, how gender influences response to asthma treatments in routine clinical practice have not yet been elucidated fully. This aspect is crucial for montelukast considering the jeopardization of asthmatic patients that benefit from this treatment and the existence of evidence of gender differences in leukotriene levels. Therefore, to fulfill this medical need, we investigated the role of gender on a set of montelukast' effectiveness surrogates in adults and pediatric patients with asthma.Methods: The study settings were Napoli 2 Local Health Unit (southern Italy) and the entire Danish territory. The study population was composed of adult and pediatric patients with asthma. Cumulative incidence curves, unadjusted and adjusted Cox regression were used as statistical models to compare aforementioned outcomes between genders.Results: Adult Italian male users of montelukast had a statistically lower persistence in montelukast treatment compared to female users. In the adjusted analyses, they had a higher hazard of montelukast' withdrawal (Hazard Ratio [HR] 1.07; 95% Confidence Interval [CI] 1.01–1.14), add-on/switch to a long-term treatment for asthma following montelukast withdrawal (HR 1.72; 95%CI 1.39–2.12), and rescue therapy with short-acting β2 agonist (HR 1.24; 95%CI 1.04–1.47). In the adult Danish cohort, we also found that male users had higher a hazard of rescue therapy with oral corticosteroids (HR 1.10; 95%CI 1.04–1.16). In the pediatric cohorts, no statistically significant differences were observed between genders for aforementioned outcomes.Conclusions: In adults, male gender was associated with increased hazards of montelukast discontinuation, add-on/switch to a long-term treatment for asthma following montelukast withdrawal, and rescue therapy with oral corticosteroids or short-acting β2 agonist when compared to the female gender. As expected, these associations were reversed or absent in pediatric patients.

Montelukast Improves Symptoms and Lung Function in Asthmatic Women Compared With Men

“…Such gender differences in LT synthesis may affect the greater severity of inflammatory responses in women compared with men. In fact, during inflammatory reactions, androgens influence 5-lipoxygenase (5-LO)-mediated cellular events (Sessa et al, 2018), inducing lower LT biosynthesis in men compared with women (Rossi et al, 2019). Based on this evidence, some study suggested that the gender could play a role on the effectiveness of anti-asthmatic pharmacological treatments, such as montelukast (MS).…”

“…Based on this evidence, some study suggested that the gender could play a role on the effectiveness of anti-asthmatic pharmacological treatments, such as montelukast (MS). Currently, it is unknown whether gender differences could have an effect on the asthmatic symptoms, pulmonary function, and biomarkers associated with the severity of asthma [e.g., eosinophils and exhaled nitric oxide (FeNO)] (Sessa et al, 2018) in the adult population. MS is the most widely used cysteinyl leukotriene (cys-LT) receptor antagonist in Europe (Theron et al, 2014).…”

“…It has both anti-inflammatory and bronchodilator activities, and it is widely used in the treatment of asthma. MS has been observed to be more efficient in the control of the asthma symptoms in girls reaching the puberty, compared with age-matched boys (Harmanci, 2007; Sessa et al, 2018). On the other hand, several studies (Pedersen et al, 1997; Biernacki et al, 2005; Burke et al, 2016) have shown that not all the asthmatic patients treated with MS experience a significant clinical improvement, and no factors have been identified to reliably predict the clinical response to cys-LT antagonists.…”

Beta-blocker choice and exchangeability in patients with heart failure and chronic obstructive pulmonary disease: an Italian register-based cohort study

“…Therefore, we may have classified patients with asthma as having chronic obstructive pulmonary disease. We believe that the magnitude of this type of misclassification is very low because Caserta Local Health unit databases contain information on drugs reimbursed by the national health system, and most of the reimbursed drugs in this ATC group are indicated for chronic obstructive pulmonary disease as shown elsewhere 36 . Additionally, beta-blockers are relatively contraindicated in asthma.…”

Montelukast induces beneficial behavioral outcomes and reduces inflammation in male and female rats

“…Furthermore, Fujiwara et al ( 121 ) found in a randomized, double-blind, placebo-controlled trial that MTK was effective in reducing dysmenorrheal pain in women. Numerous studies reported on the bidirectional association between LT function and the estrous cycle and reproductive system ( 116 , 122 – 124 ). Therefore, it is feasible that the blatant sex-associated differences in our study are affiliated with the relating female hormonal processes involved, and stratified analyzation of this parameter may have yielded interesting outcomes.…”