Z-Drug Use and All-Cause Mortality: A Meta-Analysis of Observational Cohort Studies

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.

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.

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.

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.