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Comparative Study
. 2025 Jun 24;15(1):211.
doi: 10.1038/s41398-025-03439-8.

Comparative efficacy and safety of daridorexant, lemborexant, and suvorexant for insomnia: a systematic review and network meta-analysis

Taro Kishi  1 , Toshikazu Ikuta  2 , Leslie Citrome  3 , Kenji Sakuma  4 , Masakazu Hatano  4   5 , Shun Hamanaka  4 , Yasufumi Nishii  4 , Nakao Iwata  4
Affiliations
Comparative Study

Comparative efficacy and safety of daridorexant, lemborexant, and suvorexant for insomnia: a systematic review and network meta-analysis

Taro Kishi et al. Transl Psychiatry. .

Abstract

Background: In order to appraise the risk-benefit balance of the three available dual orexin receptor antagonists (DORAs; daridorexant, lemborexant, and suvorexant) for the management of adults with insomnia, we conducted a systematic review and random-effects model network meta-analysis.

Methods: Included were all published double-blind, randomized, placebo-controlled trials of these agents. Outcomes included subjective time to sleep onset at month 1 (sTSO, primary), subjective total sleep time at month 1 (sTST, co-primary), subjective wake after sleep onset at month 1, Insomnia Severity Index scores at month 1, all-cause discontinuation, discontinuation due to adverse events, and the incidence of individual adverse events such as somnolence, dizziness, falls, headache, nasopharyngitis, and upper respiratory tract infection.

Results: This meta-analysis included eight trials (5198 adults, average age = 56.33 years, 67.84% female). The treatment arms included daridorexant 25 mg/day (DAR25), daridorexant 50 mg/day (DAR50), lemborexant 5 mg/day (LEM5), lemborexant 10 mg/day (LEM10), suvorexant 20 mg/day (15 mg/day for people ≥65years, SUV20/15), and placebo. All active-treatments outperformed placebo in terms of all efficacy outcomes. The standardized mean difference (95% CI) in primary outcomes ranged from; sTSO: -0.430 (-0.568, -0.292) for LEM10 to -0.164 (-0.296, -0.031) for SUV20/15 and sTST: -0.475 (-0.593, -0.357) for DRA50 to -0.206 ( -0.330, -0.082) for LEM5. An additional sensitivity analysis suggested that DRA25, LEM10, and SUV20/15 were associated with a higher incidence of somnolence compared to a placebo.

Conclusions: Considering that there is no evidence that DORAs are associated with physiological tolerance, withdrawal symptoms, or rebound insomnia when abruptly discontinued, and that sleep architecture is not adversely affected, the DORAs appear to be a favorable choice in managing insomnia disorder in adults.

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Conflict of interest statement

Competing interests: All authors have no competing interests to declare concerning this study. They also declare any potential competing interests that have arisen in the last 3 years. Prof. Kishi has received speaker’s honoraria from Eisai, Janssen, Boehringer Ingelheim, Meiji, Otsuka, Sumitomo, Takeda, Mitsubishi-Tanabe, Kyowa, Yoshitomi, and Viatris and research grants from Eisai, a Fujita Health University School of Medicine Research Grant, JSPS KAKENHI (19K08082 and 23K06998), Japan Agency for Medical Research and Development (JP22dk0307107, JP22wm0525024, JP23dk0307122, and 24dk0307129), and the Japanese Ministry of Health, Labour and Welfare (21GC1018). Dr. Ikuta has nothing to disclose. Prof. Citrome serves as consultant to AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, Biogen, BioXcel, Bristol-Myers Squibb /Karuna, Boehringer Ingelheim, Cadent Therapeutics, Cerevel, Clinilabs, COMPASS, Delpor, Eisai, Enteris BioPharma, HLS Therapeutics, Idorsia, INmune Bio, Impel, Intra-Cellular Therapies, Janssen, Lundbeck, Luye, Lyndra, MapLight, Marvin, Medavante-ProPhase, Merck, Mitsubishi-Tanabe Pharma, Neumora, Neurocrine, Neurelis, Noema, Novartis, Noven, Otsuka, Ovid, Praxis, Recordati, Relmada, Reviva, Sage, Sumitomo/Sunovion, Supernus, Teva, University of Arizona, Vanda, Wells Fargo, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research; speaker for AbbVie/Allergan, Acadia, Alkermes, Angelini, Axsome, BioXcel, Bristol-Myers Squibb, Eisai, Idorsia, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Recordati, Sage, Sunovion, Takeda, Teva, and CME activities organized by medical education companies such as Medscape, NACCME, NEI, Vindico, and Universities and Professional Organizations/Societies; owns stocks (small number of shares of common stock): Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer purchased >10 years ago, stock options: Reviva; and receives royalties/publishing income from Taylor & Francis (Editor-in-Chief, Current Medical Research and Opinion, 2022-date), Wiley (Editor-in-Chief, International Journal of Clinical Practice, through end 2019), UpToDate (reviewer), Springer Healthcare (book), Elsevier (Topic Editor, Psychiatry, Clinical Therapeutics). Dr. Sakuma has received speaker’s honoraria from daiichisankyo, Eisai, Janssen, Kyowa, Meiji, Otsuka, Sumitomo, and Takeda and has received a Fujita Health University School of Medicine Research Grant for Early-Career Scientists, Grant-in-Aid for Young Scientists (B)(19K17099), Grant-in-Aid for Scientific Research (C)(23K06998), and Japan Agency for Medical Research and Development (JP22dk0307107 and JP23dk0307122). Dr. Hatano received the speaker’s honoraria from Meiji and Sumitomo, and has received Grant-in-Aid for Early-Career Scientists (23K14827). Dr. Hamanaka has received speaker’s honoraria from Meiji, Otsuka, and Sumitomo. Dr. Nishii has received speaker’s honoraria from Meiji, Otsuka, and Sumitomo. Prof. Iwata has received speaker’s honoraria from Eisai, Janssen, Meiji, Otsuka, Sumitomo, Takeda, Mitsubishi-Tanabe, and Viatris and research grants from Daiichi Sankyo, Eisai, Meiji, Otsuka, Sumitomo, Takeda, Tanabe-Mitsubishi, Grant-in-Aid for Scientific Research (B)(22H03003), and Japan Agency for Medical Research and Development (JP22wm0425008).

Figures

Fig. 1
Fig. 1
Flow chart of the literature search and study selection.
Fig. 2
Fig. 2. Forest plot.
A sTSO at month 1. B sTST at month 1. C sWASO at month 1. D ISI score at month 1. 95% CI: 95% confidence interval, DAR25 daridorexant 25 mg/day, DAR50 daridorexant 50 mg/day, ISI insomnia severity index, LEM5 lemborexant 5 mg/day, LEM10 lemborexant 10 mg/day, SMD standardized mean difference, sTSO subjective time to sleep onset, sTST subjective total sleep time, SUV20/15 suvorexant 20 mg/day (15 mg/day for people >65years), sWASO subjective wake after sleep onset.
See this image and copyright information in PMC

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