Pharmacological treatment for obstructive sleep apnea: A systematic review and meta-analysis

Highlights • Obstructive sleep apnea affects one billion people worldwide and is associated with cardiometabolic risk and cognitive impairment.• Drug therapy for the management of sleep apnea has been investigated, but no robust evidence that supports its benefits has been found to date.• The combination of noradrenergic and antimuscarinic drugs shows promising results.


Introduction
Obstructive Sleep Apnea (OSA) is a condition in which repetitive upper airway closure occurs during sleep, leading to decreased oxygen saturation and impaired sleep architecture. 1It is estimated to affect one billion people worldwide 2 and is associated with cardiometabolic risk and cognitive impairment. 3ere are many treatments for OSA, such as behavioral measures, myofascial exercises, oral appliances, surgeries, Positive Airway Pressure (PAP), and hypoglossal nerve stimulators. 4Although PAP treatment remains the leading choice for moderate and severe OSA, its adherence rate is low. 5ecent research on the pathophysiology brought light to possible targets for pharmacotherapy. 6The OSA pathophysiological traits *Corresponding author.E-mail address: anakatherine_ufrnet@yahoo.com.br(A.K. Gonçalves).(endotypes) are the anatomy of the upper airway susceptible to collapse; the poor pharynx dilator muscle responsiveness; the low arousal respiratory threshold; and the oversensitive ventilatory control system (high loop gain). 7rug therapy for the management of sleep apnea has been investigated, but no robust evidence that supports its benefits has been found to date. 8e aim of this systematic review and meta-analysis is to summarize the evidence on pharmacotherapy for the treatment of OSA in adults.

Methods
This review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 9The protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42022362639).

Inclusion criteria
Randomized Clinical Trials (RCT) compared the Apnea-Hypopnea Index (AHI) of pharmacotherapies for adults with OSA.
-Intervention: Any drug therapy intended to treat OSA.
-Type of study: RCT.

Patient and public involvement
There was no patient or public involvement.

Search strategy
PubMed, Embase, Scopus, Web of Science, SciELO, LILACS, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.govwere searched with no limitations to date or language.All electronic databases were searched on February 2023.The search strategy to be used in PubMed is presented in Table 1.

Data collection and analysis
The articles were imported to Rayyan, and duplicates were removed.Two authors independently screened by title, abstract, and full text to determine inclusion criteria.A third reviewer resolved the discrepancies.

Data extraction and management
Two independent authors extracted data from the included studies.The latter were inserted into a database.Meta-analysis was conducted for the studies that could be combined.

Risk of bias assessment
Two reviewers independently assessed the risk of bias using the Cochrane Risk of Bias Tool (RoB 2). 10 Each study was evaluated for the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results.

Assessment of heterogeneity
The I 2 statistics were used to assess heterogeneity, below 25 % was considered low heterogeneity, between 25 % and 50 % moderate heterogeneity, and above 50 % high heterogeneity.
Measures of the treatment effect AHI was extracted as a continuous variable, and the mean difference with a 95 % Confidence Interval was used.This was performed using Review Manager (RevMan 5.4) software.

Analysis
RevMan 5.4 was used to perform the statistical analysis.In the heterogeneity assessment, when I 2 was > 50 %, a random-effects model was used, otherwise, a fixed-effect model was applied.

Grading quality of evidence
The Grading of Recommendations Assessment Development and Evaluation (GRADE) approach was used to evaluate the strength of the evidence of the systematic review results. 11

Results
The database search retrieved 4930 articles, duplicates were removed, and two independent authors screened 3900 titles, 319 were assessed for eligibility by abstract.68 of which met the inclusion criteria, and finally, 29 studies could be combined in the meta-analysis (11 drugs).The PRISMA flow diagram summarizes the selection process (Fig. 1).Qualitative synthesis is shown in Table 2.

Upper airway anatomy
A few different drug mechanisms can potentially target the collapsibility of the upper airway, such as weight loss medication that can reduce fat tissue on the tongue base and neck, diuretics reducing fluid retention, and nasal obstruction can be approached with intranasal steroids and decongestants. 6[14][15][16] Fig. 3. Risk of bias of the studies included in the metaanalysis.

Risk of bias assessment
The majority of the studies included were double-blind randomized control trials with an overall low risk or with some concerns of bias (Fig. 3).The strength of the evidence was assessed by GRADE (Fig. 4).
Historically, the use of drugs that would increase the arousal threshold in patients was thought to worsen apnea by decreasing muscle dilator response and promoting collapsibility.][36][37] It is important to frame that this study only brings data from primary studies that met the defined inclusion criteria and could be combined in a meta-analysis.A limitation is that drugs that have been tested by a single RCT have not been included.There is also heterogeneity among populations included in different trials that were combined, such as different degrees of OSA severity which may impact drug efficacy.
Moreover, to better understand physio-pathological endotypes other outcomes such as loop gain, arousal threshold, muscle compensation, and hypoxic burden could be assessed.

Conclusion
While numerous drugs have been investigated, only a few have shown promising results, like the combination of noradrenergic and antimuscarinic drugs.Identifying endotypes that respond to each pharmacological mechanism may be the key to future drug therapies for OSA.Moreover, studies with longer follow-up periods assessing the safety and sustained effects of these treatments are needed.

Fig. 1 .
Fig. 1.Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the selection process.

Fig. 2 .
Fig. 2. Forest plots illustrating apnea-hypopnea index mean difference in different drug therapies for obstructive sleep apnea against placebo.

Table 1
Search Strategy for PubMed.

Table 2
Qualitative synthesis of the included studies.