Terapias farmacológicas com alvo nos endotipos dos pacientes com apneia obstrutiva do sono

Abstract

Introduction: Sleep is crucial for the proper functioning of the human body. Sleep disorders can significantly impact the quality of life and increase the risk of cardiometabolic, psychiatric, and cognitive diseases. Obstructive sleep apnea (OSA) is characterized by repetitive partial or complete collapse of the upper airway during sleep. While positive airway pressure therapy is the primary treatment, its low compliance rate has prompted exploration into alternative approaches. Recent physiological studies about the disease’s mechanisms brought the possibility of therapeutic targets for pharmacotherapy. Objective: This study aims to assess and summarize the scientific evidence regarding the efficacy and safety of drug therapies in alleviating the severity of obstructive sleep apnea in adults. Methods: One protocol and two systematic reviews, one incorporating network meta-analysis, were conducted following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. A comprehensive search strategy retrieved relevant randomized clinical trials on drug treatments assessing the primary outcome apnea-hypopnea index (AHI) in adult patients with obstructive sleep apnea, from databases: PubMed, Embase, Web of Science, SciELO, LILACS, Scopus, Cochrane Register of Controlled Trials, and ClinicalTrials.gov. Two authors independently selected studies and extracted data. The Cochrane Risk of Bias tool 2 assessed the risk of bias. Pairwise meta-analysis used RevMan 5.4, while network meta-analysis utilized the netmeta package in R Studio. Results: Among the 4930 articles obtained, 68 met the inclusion criteria. A total of 29 studies, involving 11 drugs, were included in the meta-analysis. Notable findings include Atomoxetine plus oxybutynin vs placebo, demonstrating a mean difference in AHI of -7.71 (-10.59, -4.83) [Fixed, 95% CI, I2= 50%, overall effect: Z = 5.25, p<0.001]. Donepezil vs placebo exhibited a mean difference in AHI of -8.56 (-15.78, -1.33) [Fixed, 95% CI, I2= 21%, overall effect: Z= 2.32, p=0.02]. Sodium oxybate vs placebo resulted in a mean difference in AHI of -5.50 (-9.28, -1.73) [Fixed, 95% CI, I2= 32%, overall effect: Z = 2.86, p=0.004]. Trazodone vs placebo displayed a mean difference in AHI of -12.75 (-21.30, -4.19) [Fixed, 95% CI, I2= 0%, overall effect: Z = 2.92, p=0.003]. In the network meta-analysis, multiple treatments targeting muscle responsiveness in adults with obstructive sleep apnea were compared, with five interventions showing a statistically significant reduction in apnea-hypopnea index compared to placebo. Conclusions: Acetazolamide, reboxetine plus oxybutynin, atomoxetine plus oxybutynin, atomoxetine plus aroxybutynin, atomoxetine alone, donepezil, sodium oxybate and trazodone showed statistically significant reduction in AHI. The combination of noradrenergic and antimuscarinic agents emerges as the most promising drug treatment targeting muscle responsiveness. The path towards precision medicine in treating obstructive sleep apnea involves understanding endotypes, phenotypes, and developing relevant metrics. More studies to assess clinical significance, adverse events and sustained effects of these treatments in larger populations and with longer follow-ups are needed