Improvement of glycemic control by treatment for insomnia with suvorexant in type 2 diabetes mellitus

Abstract

Introduction: Acute and chronic insomnia can exacerbate type 2 diabetes mellitus (T2DM). We investigated suvorexant (an anti-insomnia drug that targets the orexin system) effects on sleep architecture and glucose metabolism in T2DM patients with insomnia.

Materials and methods: This 7 day open-label, single-arm, intervention trial included 18 subjects with T2DM and insomnia. After 1 day acclimatization, daily glucose levels, sleep architecture, and autonomic nervous function were evaluated by continuous glucose monitoring (CGM), single-channel electroencephalography, and accelerometry, respectively.

Results: Suvorexant treatment for 3 days significantly increased total sleep time and sleep efficiency, with partial suppression of sympathetic nerve activity. CGM-measured 24 h mean glucose level decreased significantly from 157.7 ± 22.9 to 152.3 ± 17.8 mg/dL, especially in the early glucose surge after the midnight nadir (from 28.3 ± 15.0 to 18.2 ± 9.9 mg/dL), and until supper with a significant improvement in homeostasis model assessment of insulin resistance from 4.0 ± 2.8 to 2.9 ± 1.6, respectively.

Conclusions: Suvorexant treatment for insomnia of subjects with T2DM significantly improved CGM-measured daily glycemic control, which was associated with changes in sympathomimetic tone and/or improved insulin sensitivity. The amelioration of insomnia may therefore be a target for improving glycemic control in T2DM patients with insomnia.

Keywords: AHI, Apnea–Hypopnea Index; AUC, area under the curve; Autonomic nervous function; BMI, body mass index; CGM, continuous glucose monitoring; CPR, C-peptide immunoreactivity; CVR-R, coefficient of variation of RR intervals; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; Dawn phenomenon; EEG, electroencephalography; Glycemic control; HOMA-IR, homeostasis model assessment of insulin resistance; HR, heart rate; HRV, heart rate variability; HbA1c, glycated hemoglobin A1c; IQR, interquartile range; IRI, immunoreactive insulin; Insulin resistance; PSQI, Pittsburgh Sleep Quality Index; REM, rapid eye movement; SAS, Sleep Apnea Syndrome; SD, standard deviation; SDNN, standard deviation of the NN (i.e., R-R) intervals; T2DM, type 2 diabetes mellitus; Therapy for insomnia; Type 2 diabetes mellitus; bpm, beats per minute; eGFR, estimated glomerular filtration ratio.

Fig. 1

Outline of the study protocol. On Day 0, the subject’s insomnia was assessed according to DSM-5 and PSQI and the subject was acclimatized to CGM. On Days 1–3, the subject took no insomnia medication. On Days 4–6, suvorexant (15 or 20 mg for subjects 65 and ≤65 years, respectively) was taken at 10:00 PM just before bedtime. On Days 3 and 6, the subject underwent measurements using single-channel EEG, portable SAS monitoring, and an accelerometer. The subject’s DM medications and daily caloric intake were kept unchanged throughout the study period. CGM, continuous glucose monitoring; DM, diabetes mellitus; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; EEG, electroencephalography; PSQI, Pittsburgh Sleep Quality Index.

Fig. 2

Comparison of EEG-assessed sleep quality and autonomic nervous system function before and after insomnia therapy in 18 subjects with T2DM and insomnia. Treatment with suvorexant significantly increased the median total sleep time (p = 0.012) with increases in both REM sleep time (p = 0.011) and non-REM sleep time (p = 0.049). As a result, median sleep efficiency increased significantly (p = 0.041). As well as, median SDNN increased significantly (p = 0.044), and median CVR-R showed a tendency to increase (p = 0.059). ^*p < 0.05 before versus after therapy (Wilcoxon signed-rank test). EEG, electroencephalography; T2DM, type 2 diabetes mellitus; REM, rapid eye movement; SDNN, standard deviation of the NN (R-R) interval; CVR-R, coefficient of variation of R-R intervals.

Fig. 3

CGM-measured glucose levels before and after therapy for insomnia. Following treatment with suvorexant, the mean glucose levels of the 18 subjects decreased pre-breakfast, with this decrease maintained until just before dinner. CGM, continuous glucose monitoring.

Fig. 4

Comparison of the dawn phenomenon before and after insomnia therapy in the 18 subjects. Mean values of the dawn phenomenon significantly decreased after insomnia therapy (^*p = 0.002; Wilcoxon signed-rank test). Of the 14 subjects who initially exhibited a positive dawn phenomenon (a morning glucose elevation >20 mg/dL), only 8 remained positive after the insomnia treatment.