Abstract and Introduction
Abstract
Background: An increased risk of fracture has been reported in older adults taking hypnotics. However, few studies have reported the comparative safety of hypnotics with different mechanisms of action. We examined the risk of fracture in older adults initiating suvorexant compared to those initiating Z-drugs.
Methods: We conducted a retrospective cohort study using a claims database within a longevity improvement and fair evidence (LIFE) study in Japan (1.5 million beneficiaries). People aged ≥65 years were included in this study. Exposure was defined as the initiation of either suvorexant or Z-drugs (eszopiclone, zolpidem, or zopiclone). The evaluated outcomes were hip fracture and all-cause fracture requiring hospitalization. We used inverse probability of treatment weights to adjust for confounding and followed the incidence of the outcome for three different periods: 30, 90, and 365 days. Cox proportional hazards models were fitted to the weighted population to estimate hazard ratios (HRs). Sensitivity analyses were performed with narrowed outcome definitions and inverse probability of censoring weights.
Results: We identified 16,148 suvorexant new users and 54,327 Z-drugs new users. During the 30-day follow-up, 21 (16.6 events per 1000 person-years) and 53 hip fractures (12.2 events per 1000 person-years) were identified among suvorexant and Z-drugs new users, respectively (HR: 1.01, 95% confidence interval [CI]: 0.58–1.76). The analysis for all-cause fracture showed an HR of 1.03 (95% CI: 0.78–1.36). Extended follow-up (90 and 365 days) showed similar results for both outcomes. Sensitivity analyses showed consistent results except for an increased risk of all-cause fracture requiring surgery (HR: 1.41, 95% CI: 0.87–2.29) during the 30-day follow-up.
Conclusions: This is the first study to show that suvorexant has a generally comparable risk of fracture as compared to Z-drugs. Further research is needed to investigate the potential short-term increased risk of all-cause fracture requiring surgery among suvorexant initiators.
Introduction
Insomnia is a prevalent problem in older adults (i.e., those aged ≥65 years). A previous review reported that 1) the prevalence of insomnia symptoms was approximately 33% in the general population worldwide, 2) the prevalence of insomnia diagnoses (defined according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]) ranged from 4.4% to 6.4%, and 3) insomnia symptoms increased with age.[1] A survey conducted in Canada similarly reported that the prevalence of insomnia diagnoses according to DSM-IV and the International Classification of Diseases, Tenth Revision (ICD-10) was 9.5%.[2]
The management of insomnia consists of cognitive behavioral therapy and pharmacotherapy with a variety of available pharmaceutical agents.[3] For example, a 2017 guideline published by the American Academy of Sleep Medicine described seven types of medications with different mechanisms of action to treat insomnia: orexin receptor antagonists, benzodiazepine receptor agonists (Z-drugs), benzodiazepines, melatonin agonists, heterocyclics, anticonvulsants, and over-the-counter preparations.[4] Although benzodiazepines and Z-drugs have been widely prescribed to manage insomnia, these medications cause adverse drug events, including dizziness or drowsiness, and several studies have reported an increased risk of fractures among benzodiazepines[5–7] and Z-drugs users.[8–11]
Older adults may be at special risk with regard to these adverse drug events, as the risk of fracture increases with aging due to osteoporosis[12] and hip fractures could lead to mobility restriction or excess mortality in this population.[13,14] A meta-analysis published in 2017 showed that both benzodiazepines and Z-drugs were associated with an increased risk of hip fracture in older adults and that even short-term use of these medications was also associated with an increased risk of fractures.[15] These two medications are also listed in the American Geriatrics Society Beers Criteria for potentially inappropriate medication use in older adults due to the increased risk of cognitive impairment, delirium, falls, fractures, and motor vehicle crashes.[16]
Dual orexin receptor antagonists (DORAs) are newly developed hypnotics. Two medications in this class have been approved in Japan (suvorexant in 2014 and lemborexant in 2020). Based on their effects on orexin receptors, it is expected that patients with sleep maintenance insomnia or sleep onset difficulty would benefit from this class of medications.[17] Moreover, clinical trials and reviews have reported that suvorexant is generally well tolerated, with only mild adverse drug events such as somnolence.[18,19] In addition, clinical trials have shown that suvorexant does not appear to cause physical dependence with chronic use.[18] Practitioners may prefer suvorexant over benzodiazepines or Z-drugs as the latter medications carry a risk of physical dependence.[20]
Although DORAs have been widely prescribed to patients (including older adults) with insomnia symptoms, their safety in comparison to that of Z-drugs and benzodiazepines has not been well studied. In this study, we did not compare suvorexant and benzodiazepines due to two reasons. First, some benzodiazepines (such as etizolam) are prescribed for anxiety disorder in Japan; therefore, differing indications would confound the comparison of suvorexant and benzodiazepines. Second, the clinical guideline for the proper use and cessation of hypnotics (published by the Japanese Society for Sleep Research) recommends Z-drugs over benzodiazepines for treating primary insomnia in older adults.[21]
Thus, in the present study, we examined the comparative safety of suvorexant and Z-drugs among community-dwelling older adults in Japan, with a focus on hip fracture and all-cause fracture as examples of safety profiles.
J Am Geriatr Soc. 2023;71(1):109-120. © 2023 Blackwell Publishing
