CONFLICT OF INTEREST
None to declare.
To the EditorThe National Health and Nutrition Examination Survey, 2005 to 2008, indicated an association between a combination of sleep problems and hypertension and also suggested the necessity of prospective studies to understand the complex interplay between them.1 The following prospective study showed that short sleep (total sleep duration < 6 hours) was independently associated with a higher risk of developing hypertension among middle‐aged and elderly Korean adults.2 A very recent meta‐analysis revealed that poor sleep quality was significantly associated with a greater likelihood of hypertension (odds ratio, 1.48; P value = .01), suggesting a significant association between sleep quality and hypertension.3
Suvorexant, an orexin receptor antagonist, has been approved as a drug for the treatment of insomnia and widely used to date in Japan. The daily resting‐phase administration of suvorexant improved glucose metabolism in db/db mice, without affecting body weight, food intake, and insulin sensitivity,4 proposing a beneficial effect of suvorexant on metabolic parameters in animal models. However, effects of suvorexant on blood pressure and metabolic parameters in humans remain unknown.
To understand effects of suvorexant on blood pressure and metabolic parameters, we compared blood pressure and metabolic parameters at baseline with values after the start of suvorexant. Briefly, we retrospectively picked up patients who had been prescribed suvorexant between September 2014 and May 2017 and whose blood pressure and metabolic parameters before and after taking suvorexant were measured. Comparison between values before and after the start of suvorexant was performed by using paired t test; correlation between changed values of each parameter was performed by using Spearman's correlation, and P < .05 was considered to be statistically significant. This study was approved by the Institutional Ethics Committee in National Center for Global Health and Medicine and was also performed in accordance with the Declaration of Helsinki.
During observation period, 88 patients (age, 59.0 ± 18.0 (mean ± SD) years; male/female, 34/54) were prescribed suvorexant. Changes in body weight and blood pressure are shown in Table 1. Body weight significantly increased at 10 months, and systolic and diastolic blood pressures significantly increased at 2 and 4 months after the start of suvorexant, respectively. Hemoglobin A1c (HbA1c) and low‐density lipoprotein cholesterol (LDL‐C) significantly increased at 8 months and 1 month after the start of suvorexant, respectively (Table 2). Surprisingly, suvorexant significantly reduced high‐density lipoprotein cholesterol (HDL‐C) at 3, 4, 6, 8, and 9 months after its start. Furthermore, HDL‐C showed a decrease (significant and nonsignificant) at every time point. Change in HDL‐C at 1 month after the start of suvorexant was significantly and negatively correlated with change in triglyceride 1 month after (r = −.463, P = .008); however, such correlation was not observed at any other time points. Changes in HDL‐C were not correlated with changes in body weight, systolic and diastolic blood pressures, HbA1c, and LDL‐C at any time points.
Table 1.
Changes of body weight and blood pressure after the start of suvorexant
| Body weight (kg) | Systolic blood pressure (mm Hg) | Diastolic blood pressure (mm Hg) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Baseline | Values after the start of suvorexant | P value | n | Baseline | Values after the start of suvorexant | P value | n | Baseline | Values after the start of suvorexant | P value | |
| After 1 mo | 15 | 59.6 ± 14.2 | 60.2 ± 13.5 | .107 | 14 | 124.9 ± 11.9 | 126.0 ± 18.1 | .78 | 14 | 75.1 ± 11.5 | 73.1 ± 13.5 | .589 |
| 2 mo | 17 | 63.6 ± 16.5 | 64.0 ± 15.8 | .461 | 15 | 122.5 ± 7.2 | 129.7 ± 8.9 | .02 | 15 | 70.8 ± 12.5 | 74.9 ± 11.0 | .052 |
| 3 mo | 9 | 60.9 ± 14.9 | 61.5 ± 15.5 | .406 | 9 | 130.7 ± 16.3 | 117.4 ± 23.0 | .098 | 8 | 73.8 ± 16.5 | 73.4 ± 8.4 | .942 |
| 4 mo | 12 | 63.5 ± 17.9 | 64.2 ± 17.3 | .504 | 9 | 123.9 ± 13.9 | 129.2 ± 9.2 | .22 | 9 | 61.9 ± 12.0 | 69.7 ± 7.7 | .02 |
| 5 mo | 8 | 55.8 ± 13.1 | 58.1 ± 12.3 | .113 | 8 | 133.1 ± 11.1 | 127.9 ± 7.8 | .18 | 8 | 67.8 ± 10.6 | 72.5 ± 10.8 | .109 |
| 6 mo | 8 | 63.9 ± 21.6 | 64.6 ± 20.2 | .676 | 10 | 128.3 ± 17.7 | 127.2 ± 16.4 | .87 | 10 | 68.7 ± 17.5 | 70.1 ± 9.6 | .8 |
| 7 mo | 7 | 53.1 ± 13.2 | 54.9 ± 13.1 | .212 | 9 | 125.8 ± 11.4 | 148.4 ± 42.0 | .14 | 9 | 64.8 ± 15.0 | 73.0 ± 19.8 | .102 |
| 8 mo | 6 | 61.8 ± 19.4 | 64.8 ± 19.1 | .056 | 10 | 132.9 ± 12.7 | 130.3 ± 13.7 | .563 | 10 | 69.5 ± 16.9 | 74.0 ± 10.1 | .271 |
| 9 mo | 5 | 59.9 ± 18.9 | 58.4 ± 18.1 | .465 | 8 | 123.8 ± 14.0 | 127.4 ± 19.3 | .557 | 8 | 65.1 ± 12.2 | 66.6 ± 11.7 | .712 |
| 10 mo | 5 | 65.9 ± 26.0 | 67.7 ± 26.8 | .04 | 7 | 126.1 ± 10.1 | 125.3 ± 7.6 | .873 | 7 | 69.4 ± 16.1 | 73.4 ± 16.5 | .145 |
| 11 mo | 3 | 51.5 ± 20.5 | 51.6 ± 18.5 | .961 | 3 | 132.0 ± 16.5 | 127.7 ± 15.6 | .416 | 3 | 60.7 ± 6.5 | 58.7 ± 19.3 | .833 |
| 12 mo | 2 | 66.0 ± 1.4 | 65.0 ± 1.4 | ND | 5 | 128.0 ± 13.2 | 125.8 ± 12.2 | .788 | 5 | 67.4 ± 20.0 | 69.0 ± 17.9 | .85 |
ND, cannot be determined.
Table 2.
Changes of hemoglobin A1c and serum lipids after the start of suvorexant
| Hemoglobin A1c (%) | Low‐density lipoprotein cholesterol (mg/dL) | Triglyceride (mg/dL) | High‐density lipoprotein cholesterol (mg/dL) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Baseline | Values after the start of suvorexant | P value | n | Baseline | Values after the start of suvorexant | P value | n | Baseline | Values after the start of suvorexant | P value | n | Baseline | Values after the start of suvorexant | P value | |
| After 1 mo | 35 | 6.8 ± 1.6 | 6.9 ± 1.6 | .173 | 41 | 92.1 ± 30.1 | 97.8 ± 33.2 | .021 | 36 | 149.3 ± 124.0 | 164.1 ± 106.8 | .432 | 36 | 58.9 ± 17.9 | 56.6 ± 17.9 | .128 |
| 2 mo | 29 | 7.2 ± 1.6 | 7.3 ± 1.8 | .597 | 37 | 98.4 ± 38.2 | 101.6 ± 38.3 | .355 | 32 | 161.2 ± 123.4 | 151.9 ± 75.9 | .713 | 31 | 61.6 ± 19.9 | 59.7 ± 18.8 | .288 |
| 3 mo | 21 | 6.7 ± 1.7 | 7.0 ± 2.2 | .311 | 23 | 100.2 ± 33.8 | 104.1 ± 31.8 | .413 | 28 | 174.0 ± 130.6 | 161.6 ± 100.9 | .619 | 25 | 58.5 ± 20.9 | 53.4 ± 22.0 | .001 |
| 4 mo | 23 | 6.9 ± 1.3 | 7.1 ± 1.8 | .353 | 27 | 102.5 ± 33.2 | 104.3 ± 35.7 | .713 | 27 | 163.3 ± 131.9 | 137.7 ± 75.3 | .347 | 24 | 63.2 ± 19.9 | 60.1 ± 20.2 | .039 |
| 5 mo | 20 | 6.7 ± 1.3 | 7.1 ± 1.9 | .067 | 21 | 98.4 ± 33.0 | 98.9 ± 27.1 | .926 | 24 | 177.4 ± 140.1 | 171.1 ± 95.3 | .833 | 18 | 56.1 ± 18.2 | 54.4 ± 22.3 | .558 |
| 6 mo | 13 | 6.6 ± 1.3 | 7.1 ± 2.0 | .068 | 19 | 100.9 ± 41.4 | 104.8 ± 39.1 | .452 | 18 | 145.9 ± 71.5 | 147.2 ± 77.0 | .949 | 19 | 63.5 ± 19.5 | 57.3 ± 17.4 | .048 |
| 7 mo | 15 | 6.9 ± 1.4 | 7.2 ± 2.2 | .257 | 20 | 92.8 ± 32.7 | 92.7 ± 24.2 | .984 | 20 | 146.9 ± 81.5 | 148.5 ± 73.1 | .929 | 21 | 59.5 ± 22.0 | 54.9 ± 17.8 | .078 |
| 8 mo | 11 | 6.4 ± 0.6 | 6.5 ± 0.8 | .039 | 15 | 107.3 ± 49.5 | 105.4 ± 39.3 | .65 | 15 | 160.5 ± 71.4 | 155.1 ± 49.6 | .686 | 15 | 57.0 ± 18.8 | 48.5 ± 13.2 | .003 |
| 9 mo | 8 | 6.4 ± 1.1 | 6.6 ± 1.1 | .235 | 5 | 101.8 ± 35.6 | 103.6 ± 31.5 | .856 | 6 | 157.8 ± 110.3 | 238.8 ± 122.6 | .068 | 9 | 51.0 ± 8.7 | 45.1 ± 10.1 | .036 |
| 10 mo | 12 | 6.5 ± 1.2 | 6.5 ± 1.4 | .697 | 12 | 96.5 ± 24.9 | 102.8 ± 35.1 | .419 | 11 | 145.0 ± 66.9 | 143.3 ± 89.9 | .952 | 12 | 54.3 ± 13.9 | 54.1 ± 13.2 | .937 |
| 11 mo | 5 | 6.1 ± 0.9 | 6.1 ± 1.1 | .553 | 3 | 110.0 ± 26.2 | 96.7 ± 31.8 | .074 | 4 | 145.5 ± 50.5 | 238.3 ± 154.7 | .187 | 5 | 46.8 ± 5.1 | 44.4 ± 10.5 | .583 |
| 12 mo | 9 | 6.1 ± 0.8 | 6.1 ± 0.8 | .479 | 6 | 99.2 ± 21.9 | 99.5 ± 26.0 | .956 | 7 | 154.1 ± 69.0 | 181.3 ± 102.3 | .506 | 8 | 54.9 ± 16.0 | 51.6 ± 13.2 | .242 |
Suvorexant is an orexin receptor antagonist, and orexin was identified as a peptide expressed in specific neurons of the lateral hypothalamic area that is stimulated by decreases in circulating glucose but inhibited by feeding‐related signals from the visceral organs.5 Orexin neurons have been reported to be regulated by monoamines and acetylcholine as well as metabolic factors including leptin, glucose, and ghrelin,6 indicating that orexin is closely associated with hormones associated with energy homeostasis and obesity. Intracerebroventricular administration of orexin reduced fasting plasma glucose levels in both normal and streptozotocin‐induced diabetic mice.7
In women with metabolic syndrome, circulating orexin was significantly associated with waist circumference, triglyceride (negative correlation), and HDL (positive correlation).8 Rapid postoperative increases in plasma orexin was reported to be associated with improvement of glucose and lipid profiles following bariatric surgery.9 However, in this study, any favorable effects of suvorexant on blood pressure and metabolic parameters were not observed, and undesirable effects such as a significant reduction of HDL‐C were observed. The underlying mechanisms for such unfavorable effects of suvorexant were completely unknown, indicating that we need further studies.
The present study has several limitations. First, other drugs, food intakes, and/or exercise levels may have an influence on the study results. Second, the number of studied subjects was small because of the limited availability. A more detailed prospective study is recommended to evaluate the effects of suvorexant on blood pressure and metabolic parameters more validly.
In conclusion, suvorexant, an orexin receptor antagonist, showed significant increases of body weight, systolic and diastolic blood pressures, and LDL‐C and also presented a significant reduction of HDL‐C.
Moriyama and Yanai contributed equally to this study.
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