Abstract Rationale Many patients with obstructive sleep apnea (OSA) continue to experience residual excessive daytime sleepiness (rEDS) despite guideline-directed therapy. Multiple wake-promoting agents are available, but their relative benefits and harms remain uncertain. Methods We conducted a network meta-analysis of randomized controlled trials evaluating approved or investigational wake-promoting agents for rEDS in adults with OSA receiving standard care. Primary efficacy outcomes were change in Epworth Sleepiness Scale (ESS) and Maintenance of Wakefulness Test (MWT). Safety outcomes included adverse events leading to discontinuation and common agent-specific events (e.g., anxiety, dizziness, dry mouth). Risk of bias was assessed with RoB 2.0. Relative rankings were derived using SUCRA. Results Across included trials, wake-promoting agents improved both ESS and MWT versus placebo. Based on the network estimates, solriamfetol and modafinil/armodafinil consistently demonstrated clinically meaningful improvements in ESS; solriamfetol tended to show larger MWT gains. Pitolisant showed modest ESS improvement with a generally favorable tolerability profile. Investigational orexin-2 agonists (e.g., danavorexon/MK-7288) showed signals of benefit, though precision was limited by smaller evidence bases. Discontinuation due to adverse events was uncommon across agents. Anxiety and dizziness were observed with some stimulatory agents; dry mouth occurred variably. Certainty of evidence ranged from low to moderate due to heterogeneity and imprecision in some comparisons. Conclusions Several wake-promoting agents appear effective for rEDS in OSA, with solriamfetol frequently ranking highly for wakefulness (MWT) and modafinil-class agents showing consistent ESS improvement; pitolisant may be an alternative for patients prioritizing tolerability. Head-to-head trials remain limited, and comparative estimates should be interpreted with appropriate caution. Future research should clarify long-term safety, patient-centered outcomes, and subgroups most likely to benefit. This abstract is funded by: None
Mahapatra et al. (Fri,) studied this question.