Ji-Yeon Park,1 Hye Jin Park,1 Hae-Jin Ko,1,2 A-Sol Kim,2,3 Ji-Eun Song,2,3 Hee-Eun Hong1 1Department of Family Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea; 2Department of Family Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 3Department of Family Medicine, Kyungpook National University Chilgok Hospital, Daegu, Republic of KoreaCorrespondence: Hae-Jin Ko, Kyungpook National University Hospital, 130 Dongdeok-ro, Jung-gu, Daegu, 41944, Republic of Korea, Tel +82-53-200-6578, Fax +82-53-200-5480, Email liveforme@knu.ac.krIntroduction: Non-benzodiazepine hypnotic drugs known as z-drugs (including zolpidem, eszopiclone, zopiclone, zaleplon) are commonly prescribed for insomnia patients worldwide. Z-drugs have been thought to be safer than benzodiazepines; however, several studies have raised controversy over the side effects of z-drug. This meta-analysis was conducted to evaluate the association between z-drugs and all-cause mortality.Methods: To evaluate the association between z-drugs and all-cause mortality, we conducted a meta-analysis of observational cohort studies identified through PubMed, Embase, and Scopus up to 14 March 2025. The study populations included clinical patients. The pooled hazard ratio of all-cause mortality was calculated using a random-effects model with corresponding 95% confidence of intervals (CI). Sensitivity analysis and subgroup analyses were also performed.Results: Nine cohort studies involving 2,018,397 participants were included for the meta-analysis. Z-drug use was significantly associated with an increased risk of overall mortality (HR = 1.600; 95% CI 1.027− 2.491; P = 0.038), with evidence of substantial heterogeneity (I = 99.642%, P < 0.001). Sensitivity analysis confirmed result stability (HRs 1.440– 1.761; all p < 0.05). Subgroup analyses showed a consistent positive trend across regions, follow-up durations, and study quality (HRs 1.120– 1.780), though not all were statistically significant.Discussion: This meta-analysis showed a positive association between z-drug use and all-cause mortality; however, the substantial between-study heterogeneity (I2 = 99.6%) warrants cautious interpretation of these findings. Clinicians should exercise caution when prescribing z-drugs to high-risk patients.Keywords: non-benzodiazepine hypnotics, zolpidem, zopiclone, eszopiclone, zaleplon
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