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Effects of the oriental herbal medicine Bofu-tsusho-san in obesity hypertension: A multicenter, randomized, parallel-group controlled trial (ATH-D-14-01021.R2)

Open AccessPublished:March 24, 2015DOI:https://doi.org/10.1016/j.atherosclerosis.2015.01.025

      Highlights

      • Obesity hypertension is a major problem associated with cardiovascular disease.
      • Development of efficient treatment strategy for obesity hypertension is needed.
      • Increased ambulatory BP variability is related to cardiovascular injury and disease.
      • Bofu-tsusho-san is an oriental herbal medicine with anti-obesity effect.
      • Bofu-tsusho-san exerted an inhibitory effect on ambulatory BP variability in obesity.

      Abstract

      Objective

      There is no clinical evidence that supports the benefit of integrative medicine, defined as combination therapy of oriental and western medicine, on obesity-related hypertension. This study evaluates the efficacy of Bofu-tsusho-san (BOF), an oriental herbal medicine, on the ambulatory blood pressure (BP) profile in hypertensive patients with obesity.

      Methods

      The study design was a multicenter, randomized, open-label, parallel-group controlled trial in 107 hypertensive patients with obesity. Participants were randomly assigned to receive either the conventional control therapy or BOF add-on therapy. In both groups antihypertensive therapy was aimed at achieving the target clinic BP. The primary outcome was change in the ambulatory BP profile from baseline to 24 weeks after randomization.

      Results

      Daytime systolic BP variability, an important parameter of ambulatory BP profile, was decreased in the BOF group, and the difference in the changes in daytime systolic BP variability was significant between the BOF and control group (Control vs BOF; the change from baseline in daytime systolic BP variability, 1.0 ± 3.3 vs −1.0 ± 3.3%; p = 0.006).

      Conclusion

      The BOF add-on therapy effectively improved the ambulatory BP variability. This is the first report suggesting that an integrative medicine approach may exert favorable effects on obesity-related hypertension compared with conventional pharmaceutical treatment.

      Clinical trial registration

      UMIN000003878.

      Keywords

      1. Introduction

      Obesity-related disease patients are increasing and obesity is a major medical problem associated with the development of hypertension, type 2 diabetes (T2DM) and dyslipidemia, and ultimately life-threatening cardiovascular disease (CVD) [
      • Ng M.
      • Fleming T.
      • Robinson M.
      • et al.
      Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013.
      ]. Obesity is reportedly often accompanied by hypertension and obesity-related hypertension is closely associated with the development of systemic atherosclerosis along with T2DM and dyslipidemia, resulting in increased CVD morbidity [
      • Landsberg L.
      • Aronne L.J.
      • Beilin L.J.
      • et al.
      Obesity-related hypertension: pathogenesis, cardiovascular risk, and treatment – a position paper of the The Obesity Society and The American Society of Hypertension.
      ]. Therefore, there is a need for new treatment strategies for the management of both obesity and hypertension. In the face of widespread and still increasing obesity, a variety of anti-obesity drugs and procedures, such as bariatric surgery, have been developed as treatments under the approach of western medicine that have helped a number of severely obese patients, but these treatment modalities are limited due to both adverse effects and the degree of invasiveness [
      • Dietrich M.O.
      • Horvath T.L.
      Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons.
      ,
      • Dixon J.B.
      • le Roux C.W.
      • Rubino F.
      • et al.
      Bariatric surgery for type 2 diabetes.
      ].
      Bofu-tsusho-san (BOF), an oriental herbal medicine, has been used for obese patients in Japan. BOF, composed of 18 crude herbal drugs (Supplemental Table 1), has been reported to exert various anti-obesity effects by stimulating adipose tissue in rodents [
      • Yoshida T.
      • Sakane N.
      • Wakabayashi Y.
      • et al.
      Thermogenic, anti-obesity effects of bofu-tsusho-san in MSG-obese mice.
      ,
      • Ono M.
      • Ogasawara M.
      • Hirose A.
      • et al.
      Bofutsushosan, a Japanese herbal (Kampo) medicine, attenuates progression of nonalcoholic steatohepatitis in mice.
      ]. With respect to active ingredients of BOF, a previous study reported that main effective components of BOF were shizonepetae spica, glycyrrhizae radix, forsythiae fructus and ephedra herba. Ephedrine contained in ephedra herba acts on sympathetic nerve terminal and promotes the release of norepinephrine. Increased norepinephrine stimulates β-receptor in adipose tissue, and induces thermogenesis in brown adipose tissue and lipolysis in white adipose tissue through increases the synthesis of cAMP. Additionally, since glycyrrhizae radix, forsythiae fructus and schizonepetae spica have a potent inhibiting effect of phosphodiesterase, degradation of cAMP is inhibited to exert more powerful anti-obesity effect described above [
      • Yoshida T.
      • Sakane N.
      • Wakabayashi Y.
      • et al.
      Thermogenic, anti-obesity effects of bofu-tsusho-san in MSG-obese mice.
      ]. In addition, we recently reported that BOF exerted a favorable effect on metabolism, including an antihypertensive effect, not only via its beneficial effect on adipose tissue function, but also its appetite inhibitory effect in a mouse model of human metabolic disorders with obesity [
      • Azushima K.
      • Tamura K.
      • Wakui H.
      • et al.
      Bofu-tsu-shosan, an oriental herbal medicine, exerts a combinatorial favorable metabolic modulation including antihypertensive effect on a mouse model of human metabolic disorders with visceral obesity.
      ]. The development of highly efficient antihypertensive drugs with fewer adverse effects based on oriental herbal medicine is an attractive research subject, and randomized controlled trials are needed to reasonably evaluate the efficacy and safety of oriental herbal medicine for treating hypertension [
      • Xiong X.
      • Yang X.
      • Liu Y.
      • et al.
      Chinese herbal formulas for treating hypertension in traditional Chinese medicine: perspective of modern science.
      ]. However, there have been no randomized clinical trials investigating possible effects of BOF on blood pressure (BP) profiles in hypertensive patients with obesity.
      Concerning the BP management, accumulating evidence supports that the “out-of-clinic” BP, particularly the ambulatory BP profile, is important for a proper diagnosis of hypertension and estimation of BP control [
      • Hodgkinson J.
      • Mant J.
      • Martin U.
      • et al.
      Relative effectiveness of clinic and home blood pressure monitoring compared with ambulatory blood pressure monitoring in diagnosis of hypertension: systematic review.
      ]. Ambulatory BP monitoring allows the acquisition of critical information not only at the level of the 24-h BP but also the BP variations that occur in the course of daily activities. Among the several parameters obtained by ambulatory BP monitoring, ambulatory BP variability reflects a complex phenomenon that involves both short- and long-lasting changes [
      • Mancia G.
      • Parati G.
      Ambulatory blood pressure monitoring and organ damage.
      ]. The 24-h BP varies not only because of a reduction in BP during nighttime sleep and an increase in the morning, but also because of sudden, quick and short-term changes that occur both during the day and, to a lesser extent, at night. This phenomenon, ambulatory short-term BP variability, has been shown to depend on sympathetic vascular modulation and on atherosclerotic vascular changes [
      • Mancia G.
      • Parati G.
      Ambulatory blood pressure monitoring and organ damage.
      ]. Recently ambulatory short-term BP variability is highlighted as an emerging parameter to assess “quality of BP control” by accumulated findings showing that hypertensive patients with similar 24-h average BP values exhibited more severe organ damage when the short-term BP variability was greater [
      • Kikuya M.
      • Hozawa A.
      • Ohokubo T.
      • et al.
      Prognostic significance of blood pressure and heart rate variabilities: the Ohasama study.
      ,
      • Shintani Y.
      • Kikuya M.
      • Hara A.
      • et al.
      Ambulatory blood pressure, blood pressure variability and the prevalence of carotid artery alteration: the Ohasama study.
      ,
      • Tatasciore A.
      • Zimarino M.
      • Tommasi R.
      • et al.
      Increased short-term blood pressure variability is associated with early left ventricular systolic dysfunction in newly diagnosed untreated hypertensive patients.
      ]. Thus, short-term BP variability is associated with cardiovascular injury and is one of important prognostic factors for CVD [
      • Parati G.
      • Ochoa J.E.
      • Lombardi C.
      • et al.
      Assessment and management of blood-pressure variability.
      ].
      In this Yokohama Combined Treatment with Oriental Herb Randomized Efficacy on Obesity Hypertension (Y-CORE) Study, we aimed to investigate whether an integrative medicine approach which combined an oriental medicine (BOF) and western medicine (dietary therapy and antihypertensive drug administration) would exerts favorable effects on the ambulatory BP profile including BP variability in hypertensive patients with obesity more efficiently than the western approach alone.

      2. Methods

      2.1 Study design

      The Y-CORE study was a multicenter, prospective, randomized, open-label, parallel-group controlled trial investigating the effects of an integrative medicine approach on hypertensive patients with obesity. It was conducted in accordance with the ethical principles of the Declaration of Helsinki and was approved by the independent ethics committee for each center. The Y-CORE study was registered at the Clinical Trial Registry of University Hospital Information Network (registration no. UMIN000003878).

      2.2 Inclusion criteria

      Hypertensive patients with obesity who had a history of antihypertensive treatment, including diet and exercise therapies for a period of more than 4 weeks, were eligible and recruited for the study if they were 20–79 years of age. Obesity was defined as a body mass index (BMI) of more than 25 kg/m2. Exclusion criteria included severe hypertension (clinic systolic BP > 180 mmHg and/or diastolic BP > 110 mmHg), secondary hypertension, a history of CVD including stroke in the past 6 months, uncontrolled type 1 or type 2 diabetes (HbA1c ≥ 9.0%), women who were nursing or pregnant, or treatment with other oriental herbal medicines.
      All of the patients provided written informed consent before participation in the study, and follow-up was undertaken by each investigator.

      2.3 Procedures

      This multicenter, prospective, randomized, open-label, parallel-group controlled trial was conducted at five hospitals in Japan, and a central source allocated randomization using a computer-generated, stratified, permuted block method was applied. The block size was 4, and the stratification factors were sex and BMI. After the run-in period, eligible patients were randomly assigned (in a 1:1 allocation ratio) either to the BOF add-on therapy group (the BOF group) or the conventional control therapy group (the control group). The core study center was located at Yokohama City University.
      In both groups, each patient received lifestyle education, including dietary guidance by a nutritionist for obesity related hypertension in order to restrict the energy intake according to their pathological conditions and needs (25–30 kcal/kg-standard body weight/day), and antihypertensive therapy was aimed at achieving the BP goal recommended in the guideline of the Japanese society of hypertension [
      • Shimamoto K.
      • Ando K.
      • Fujita T.
      • et al.
      The Japanese Society of hypertension guidelines for the management of hypertension (JSH 2014).
      ]. Patients in the BOF group were initially given 2.5 g of BOF once daily; the dose of BOF was titrated up to 7.5 g daily, as long as adverse effects appeared, during the 24-week active treatment period. Body weight, clinic BP, ambulatory BP, brachial-ankle pulse wave velocity (baPWV), laboratory measurements, adverse events, and patient's adherence to treatment regimens were estimated at baseline, and after 12 and 24 weeks of treatment.

      2.4 Measurements

      The clinic BP was measured in a sitting position using a calibrated standard mercury sphygmomanometer and the recommended cuff size. Two measurements were taken at 1–2 min intervals, and their average was regarded as the clinic BP.
      The ambulatory BP and heart rate (HR) were measured every 30 min with a fully automated device (TM-2431; A&D, RAC-3502; NIHON KOHDEN, FB-270; FUKUDA DENSHI, Tokyo, Japan), essentially as described previously [
      • Kanaoka T.
      • Tamura K.
      • Moriya T.
      • et al.
      Effects of multiple factorial intervention on ambulatory BP profile and renal function in hypertensive type 2 diabetic patients with overt nephropathy – a pilot study.
      ,
      • Kanaoka T.
      • Tamura K.
      • Ohsawa M.
      • et al.
      Effects of aliskiren-based therapy on ambulatory blood pressure profile, central hemodynamics, and arterial stiffness in nondiabetic mild to moderate hypertensive patients.
      ,
      • Kanaoka T.
      • Tamura K.
      • Wakui H.
      • et al.
      L/N-type calcium channel blocker cilnidipine added to renin-angiotensin inhibition improves ambulatory blood pressure profile and suppresses cardiac hypertrophy in hypertension with chronic kidney disease.
      ,
      • Yanagi M.
      • Tamura K.
      • Fujikawa T.
      • et al.
      The angiotensin II type 1 receptor blocker olmesartan preferentially improves nocturnal hypertension and proteinuria in chronic kidney disease.
      ]. The participants were instructed to fill out a diary to record the times of sleeping, rising and other daytime activities. Therefore, the terms “daytime” and “nighttime” in the present study reflect the average period during which the subjects were awake/upright and asleep/supine, respectively.
      Short-term BP variability is estimated as the coefficients of variation (CV) of the BP values obtained from ambulatory BP monitoring, and is calculated as the within-subject standard deviation (SD) of all the systolic and diastolic readings divided by the average BP during the course of the measurement period. HR variability, which is composed of the CV of the HR values, is also calculated as the within-subject SD of all the HR values divided by the average HR. BP and HR artifacts during monitoring were defined according to the criteria reported in our previous studies and were omitted from the analysis [
      • Kanaoka T.
      • Tamura K.
      • Wakui H.
      • et al.
      L/N-type calcium channel blocker cilnidipine added to renin-angiotensin inhibition improves ambulatory blood pressure profile and suppresses cardiac hypertrophy in hypertension with chronic kidney disease.
      ,
      • Yanagi M.
      • Tamura K.
      • Fujikawa T.
      • et al.
      The angiotensin II type 1 receptor blocker olmesartan preferentially improves nocturnal hypertension and proteinuria in chronic kidney disease.
      ].
      The baPWV values were determined with a PP analyzer (model: BP-203RPE2; Omron Healthcare, Kyoto, Japan), as described previously [
      • Kanaoka T.
      • Tamura K.
      • Ohsawa M.
      • et al.
      Effects of aliskiren-based therapy on ambulatory blood pressure profile, central hemodynamics, and arterial stiffness in nondiabetic mild to moderate hypertensive patients.
      ,
      • Azushima K.
      • Uneda K.
      • Tamura K.
      • et al.
      Effects of single pill-based combination therapy of amlodipine and atorvastatin on within-visit blood pressure variability and parameters of renal and vascular function in hypertensive patients with chronic kidney disease.
      ]. Pulse volume waveforms were recorded with sensors placed over the right brachial artery and both tibial arteries. The baPWV values obtained by this method are reported to be significantly correlated with the aortic PWV determined by the catheter method [
      • Yamashina A.
      • Tomiyama H.
      • Takeda K.
      • et al.
      Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement.
      ].

      2.5 Outcomes

      The primary outcome was change in the ambulatory BP profile including short-term BP variability from baseline to 24 weeks after randomization. Changes in clinic BP, body weight, BMI, abdominal circumference, glucose-lipid metabolism, renal function, electrolytes, adipokine, oxidative stress, and baPWV from baseline to 24 weeks after randomization, and adverse events during the active treatment period were assessed as secondary outcomes.

      2.6 Statistical analysis

      The sample size was estimated with the following assumptions; α was set at 0.05, power at 80%, and the intergroup difference in changes of ambulatory short-term systolic BP variability (CV) at 1.7%. This value for the change in short-term systolic BP variability was calculated by multiplying the body weight reduction by the ratio of changes in short-term systolic BP variability to changes in body weight in our previous study [
      • Kanaoka T.
      • Tamura K.
      • Moriya T.
      • et al.
      Effects of multiple factorial intervention on ambulatory BP profile and renal function in hypertensive type 2 diabetic patients with overt nephropathy – a pilot study.
      ]. Assuming a 20% dropout rate, a total sample size of n = 100 randomized participants was required.
      An intention-to-treat analysis was performed, including 106 of the 107 randomized subjects while excluding one subject who did not meet the inclusion criteria (Supplemental Fig. 1). All of the analyses were performed using SPSS version 19.0 (IBM Corporation). To examine the effects of BOF treatment, the change values (absolute values after the 12 or 24 week study periods minus those at baseline) were used for analysis. Significant differences between the groups were assessed by unpaired t-test or nonparametric analysis using the Wilcoxon U test for variables that were normally distributed. Differences between the groups for categorical variables, such as medication or past medical history, were analyzed using the Chi-square test. Univariate and multivariate linear regression analyses were performed to identify the factors affecting changes in the daytime systolic BP variability. Age, gender, BOF usage and the variables, which were significantly associated in the univariate analysis or were significantly different between the groups after treatment, were entered into the multivariate model. The data are mean ± SD absolute values, changes from baseline at 12 and 24 weeks, or as a percentage, and a value of p < 0.05 was considered statistically significant.

      3. Results

      3.1 Study population

      A total of 107 hypertensive patients with obesity were screened for eligibility from June 2010 to March 2013. At the inclusion visit, one of them did not fulfill the selection criteria. 106 patients were thus enrolled and randomly assigned (54 to the BOF group, 52 to the control group; Supplemental Fig. 1). Of the enrolled participants, 5 patients in the control group and 8 patients in the BOF group dropped out after the 12-week treatment and, additionally, 1 patient in the control group and 6 patients in the BOF group dropped out after the 24 week treatment (Supplemental Fig. 1). Therefore, the data on 93 patients for the interim evaluation and 88 patients for the final evaluation were available for the analysis, respectively (Supplemental Fig. 1). The baseline characteristics of the patients are shown in Table 1. The mean age, BMI, and clinic BP of the 106 patients were 59.6 ± 13.7 years old, 30.9 ± 5.0 kg/m2 and 143 ± 19/84 ± 13 mmHg, respectively. There were no significant differences in the baseline characteristics between the two groups (Table 1). Medication including the antihypertensive agents, oral glucose-lowering agents and lipid-lowering agents used at baseline and during the whole active treatment period were comparable in the two groups (Supplemental Table 2). The average dose of BOF was 6.8 ± 1.4 g per day after a period of 24 weeks of treatment.
      Table 1Baseline characteristics of the study groups.
      Control groupBOF groupp
      Gender (male/female)29/2328/260.909
      Age (year)60.0 ± 12.959.2 ± 14.50.686
      Height (cm)160.9 ± 9.1162.4 ± 8.60.546
      Body weight (kg)79.8 ± 17.382.5 ± 16.40.514
      BMI (kg/m2)30.6 ± 4.931.3 ± 5.00.407
      Abdominal circumference (cm)101 ± 10105 ± 120.063
      Clinic systolic BP (mmHg)144 ± 20142 ± 190.733
      Clinic diastolic BP (mmHg)82 ± 1585 ± 120.151
      Smoke (%)16160.966
      Alcohol (%)48310.088
      Diabetes mellitus (%)35230.194
      Lipid disorder (%)69710.830
      Previous cardiovascular event (%)260.317
      Fasting plasma glucose (mg/dL)124 ± 40112 ± 270.129
      HbA1c (%)6.1 ± 0.66.0 ± 0.60.212
      Total cholesterol (mg/dL)197 ± 32203 ± 350.335
      LDL-cholesterol (mg/dL)113 ± 25119 ± 310.309
      HDL-cholesterol (mg/dL)54 ± 1557 ± 170.418
      Triglycerides (mg/dL)219 ± 213185 ± 1330.758
      Serum creatinine (mg/dL)0.85 ± 0.290.84 ± 0.310.810
      eGFR (mL/min/1.73 m2)68.9 ± 17.971.4 ± 21.90.750
      UACR (mg/g-Cr)189.1 ± 437.2153.4 ± 325.00.283
      The values are presented as means ± SD or %. BMI, body mass index; BP, blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio.

      3.2 Primary outcome

      The effects on changes in ambulatory BP profile of BOF add-on therapy versus conventional therapy are shown in Table 2. At baseline, there were no significant differences in the ambulatory average BP level and ambulatory short-term BP variability, estimated as CV of the BP values obtained from ambulatory BP monitoring, between the two groups. In accord with the study protocol which was intended to achieve the same clinic BP goal in each group, the ambulatory average BP decreased to comparable levels in the two groups after a period of 24 weeks of treatment (Control vs BOF; daytime ambulatory average BP, 136 ± 13/82 ± 9 vs 136 ± 11/82 ± 8 mmHg; nighttime ambulatory average BP, 122 ± 14/72 ± 9 vs 123 ± 15/72 ± 9 mmHg; Table 2). Concerning the changes from baseline in the ambulatory average BP level by the respective treatments, the magnitude of decrease in the daytime diastolic BP was significantly smaller in the BOF group than in the control group after a period of 24 weeks of treatment (Control vs BOF; change in daytime diastolic BP, −3 ± 7 vs −1 ± 6 mmHg, p = 0.045; Table 2).
      Table 2Comparison of ambulatory BP profile in the control and BOF groups.
      Baseline12 weeks24 weeks
      After treatmentChangepAfter treatmentChangep
      Ambulatory BP and HR
      Daytime:
       Systolic BP (mmHg)
      Control group143 ± 12139 ± 13−4 ± 120.870136 ± 13−7 ± 120.095
      BOF group140 ± 13136 ± 12−4 ± 15136 ± 11−3 ± 11
       Diastolic BP (mmHg)
      Control group86 ± 883 ± 10−2 ± 80.66582 ± 9−3 ± 70.045
      BOF group84 ± 1081 ± 8−3 ± 882 ± 8−1 ± 6
       HR (beats/min)
      Control group73 ± 973 ± 90 ± 60.73772 ± 9−1 ± 60.119
      BOF group75 ± 1175 ± 130 ± 874 ± 131 ± 9
      Nighttime:
       Systolic BP (mmHg)
      Control group128 ± 15124 ± 16−3 ± 130.692122 ± 14−6 ± 150.885
      BOF group128 ± 18128 ± 13−2 ± 21123 ± 15−6 ± 15
       Diastolic BP (mmHg)
      Control group77 ± 1073 ± 9−3 ± 70.26972 ± 9−5 ± 80.195
      BOF group76 ± 1075 ± 10−1 ± 1072 ± 9−3 ± 7
       HR (beats/min)
      Control group63 ± 863 ± 80 ± 50.87863 ± 8−1 ± 60.430
      BOF group64 ± 1264 ± 120 ± 863 ± 121 ± 6
      Ambulatory BP and HR variability
      Daytime:
       Systolic BP variability (%)
      Control group11.5 ± 3.413.0 ± 4.91.5 ± 4.60.22612.3 ± 3.11.0 ± 3.30.006
      BOF group12.2 ± 3.312.7 ± 4.00.5 ± 3.711.4 ± 2.8−1.0 ± 3.3
       Diastolic BP variability (%)
      Control group13.8 ± 6.014.9 ± 6.11.4 ± 5.50.17814.4 ± 4.50.9 ± 6.20.135
      BOF group15.4 ± 5.515.1 ± 5.6−0.1 ± 5.214.8 ± 5.9−1.1 ± 6.4
       HR variability (%)
      Control group14.6 ± 6.613.3 ± 4.7−1.2 ± 6.90.94612.4 ± 4.4−2.3 ± 7.70.386
      BOF group16.1 ± 6.814.7 ± 5.7−1.3 ± 6.915.7 ± 5.2−0.9 ± 6.7
      Nighttime:
       Systolic BP variability (%)
      Control group10.7 ± 3.510.6 ± 3.6−0.3 ± 4.10.24910.8 ± 3.00.2 ± 4.60.885
      BOF group10.2 ± 4.010.5 ± 4.10.8 ± 4.210.8 ± 3.91.1 ± 4.7
       Diastolic BP variability (%)
      Control group13.4 ± 5.312.5 ± 3.9−0.8 ± 4.70.60512.6 ± 4.3−0.4 ± 5.60.199
      BOF group12.1 ± 4.311.5 ± 4.3−0.2 ± 5.713.0 ± 4.61.1 ± 5.5
       HR variability (%)
      Control group7.7 ± 3.17.1 ± 3.2−0.3 ± 3.50.3728.1 ± 2.70.6 ± 3.40.737
      BOF group8.1 ± 3.78.3 ± 3.00.3 ± 3.79.1 ± 4.90.9 ± 4.6
      The values are presented as means ± SD. BP, blood pressure; HR, heart rate.
      However, with respect to the effects on changes in ambulatory short-term BP variability of BOF add-on therapy versus conventional therapy, the daytime systolic BP variability was decreased only in the BOF group at 24 weeks and the difference was statistically significant between the BOF and control groups (Control vs BOF; change from baseline in daytime systolic BP variability, 1.0 ± 3.3 vs −1.0 ± 3.3%, p = 0.006; Table 2). In addition, the daytime diastolic BP variability was similarly decreased only in the BOF group at 24 weeks, but the difference did not reach the significance between the BOF and control groups (Control vs BOF; change from baseline in daytime diastolic BP variability, 0.9 ± 6.2 vs −1.1 ± 6.4%, p = 0.135; Table 2).

      3.3 Secondary outcomes

      As shown in Supplemental Table 3, there were no significant differences in the clinic BP or baPWV between the two groups at baseline. Concerning the changes from baseline in the clinic BP or baPWV by the respective treatments as additional efficacy outcomes, there were also no significant differences in the changes from baseline in the clinic BP or baPWV between the two groups during the active treatment period (Supplemental Table 3).
      Table 3 summarizes the differences in the anti-obesity effect between groups as the additional efficacy outcomes. Although each patient received lifestyle education, including dietary guidance by a nutritionist for obesity related hypertension in order to restrict the energy intake according to their pathological conditions and needs (25–30 kcal/kg-standard body weight/day) in both groups, the BOF add-on therapy efficiently reduced body weight and BMI at 12 and 24 weeks, and the differences were statistically significant between the BOF and control groups for both measures (Control vs BOF; change from baseline in body weight, −1.2 ± 2.6 vs −2.8 ± 3.5 kg, p = 0.023; change from baseline in BMI, −0.5 ± 1.0 vs −1.1 ± 1.3 kg/m2, p = 0.029; Table 3). Although abdominal circumference exhibited a similar tendency of change at 24 weeks, the difference between the BOF and control groups did not reach significance (Control vs BOF; change from baseline in abdominal circumference, −2 ± 6 vs −4 ± 6 cm, p = 0.053; Table 3).
      Table 3Comparison of body weight, BMI and abdominal circumference in the control and BOF groups.
      Baseline12 weeks24 weeks
      After treatmentChangepAfter treatmentChangep
      Body weight (kg)
       Control group79.8 ± 17.378.9 ± 17.4−0.8 ± 2.50.00778.3 ± 17.9−1.2 ± 2.60.023
       BOF group82.5 ± 16.480.5 ± 15.6−2.0 ± 2.779.6 ± 15.4−2.8 ± 3.5
      BMI (kg/m2)
       Control group30.6 ± 4.930.1 ± 5.0−0.3 ± 0.90.00529.9 ± 5.2−0.5 ± 1.00.029
       BOF group31.3 ± 5.030.3 ± 4.9−0.8 ± 1.030.3 ± 4.9−1.1 ± 1.3
      Abdominal circumference (cm)
       Control group101 ± 10100 ± 13−3 ± 40.760100 ± 12−2 ± 60.053
       BOF group105 ± 12103 ± 12−3 ± 5102 ± 11−4 ± 6
      The values are presented as means ± SD. BMI, body mass index.
      The effects of BOF add-on therapy on glucose-lipid metabolism, renal function, adipokine level, and oxidative stress as additional efficacy outcomes are summarized in Table 4. At baseline, there were no significant differences in the laboratory measurements between the two groups. BOF add-on therapy reduced HbA1c at 12 and 24 weeks, and the change at 12 weeks from baseline in HbA1c was statistically significant (Control vs BOF; change from baseline in HbA1c, 0.0 ± 0.3 vs −0.1 ± 0.2%, p = 0.038; Table 4), with a non-significant difference in the change at 24 weeks (Control vs BOF; change from baseline in HbA1c, −0.1 ± 0.4 vs −0.2 ± 0.3%, p = 0.103; Table 4). However, BOF add-on therapy exerted no evident effects on serum insulin level and HOMA-IR (data not shown). On the other hand, BOF add on therapy did not affect the change in lipid metabolism. Also, the renal function parameters including serum creatinine, estimated glomerular filtration rate (eGFR), and urine albumin-to-creatinine ratio (UACR) were comparable in the two groups during the entire active treatment period (Table 4).
      Table 4Comparison of laboratory measurements in the control and BOF groups.
      Baseline12 weeks24 weeks
      After treatmentChangepAfter treatmentChangep
      Glucose-lipid metabolism:
       Fasting plasma glucose (mg/dL)
      Control group124 ± 4118 ± 31−3 ± 330.460112 ± 27−9 ± 330.161
      BOF group112 ± 27108 ± 25−5 ± 17112 ± 28−1 ± 14
       HbA1c (%)
      Control group6.1 ± 0.66.1 ± 0.60.0 ± 0.30.0386.0 ± 0.7−0.1 ± 0.40.103
      BOF group6.0 ± 0.65.9 ± 0.6−0.1 ± 0.25.9 ± 0.6−0.2 ± 0.3
       Total cholesterol (mg/dL)
      Control group197 ± 32192 ± 34−4 ± 230.397195 ± 31−1 ± 280.556
      BOF group203 ± 35203 ± 33−1 ± 21197 ± 32−4 ± 28
       LDL-cholesterol (mg/dL)
      Control group113 ± 25113 ± 250 ± 180.794110 ± 24−2 ± 240.754
      BOF group119 ± 31121 ± 312 ± 19117 ± 27−1 ± 23
       HDL-cholesterol (mg/dL)
      Control group54 ± 1553 ± 140 ± 60.58756 ± 153 ± 70.776
      BOF group57 ± 1758 ± 151 ± 861 ± 172 ± 7
       Triglycerides (mg/dL)
      Control group219 ± 213179 ± 141−45 ± 2080.818193 ± 18−32 ± 2140.399
      BOF group185 ± 133159 ± 79−25 ± 128137 ± 53−31 ± 78
      Renal function:
       Serum creatinine (mg/dL)
      Control group0.85 ± 0.290.84 ± 0.20−0.02 ± 0.120.7490.83 ± 0.28−0.03 ± 0.130.920
      BOF group0.84 ± 0.310.81 ± 0.27−0.02 ± 0.100.80 ± 0.27−0.03 ± 0.12
       eGFR (mL/min/1.73 m2)
      Control group68.9 ± 17.973.5 ± 37.15.2 ± 32.10.51770.5 ± 19.52.5 ± 9.60.825
      BOF group71.4 ± 21.969.3 ± 26.6−2.7 ± 22.173.8 ± 24.32.8 ± 9.8
       UACR (mg/g-Cr)
      Control group189.1 ± 437.2138.5 ± 392.1−25.2 ± 282.50.896132.0 ± 362.8−35.3 ± 312.50.524
      BOF group153.4 ± 325.0159.8 ± 328.5−7.0 ± 171.5191.2 ± 408.925.4 ± 209.6
      Adipokine and oxidative stress:
       Adiponectin (μg/mL)
      Control group3.3 ± 3.03.1 ± 2.20.0 ± 1.20.5743.2 ± 2.1−0.1 ± 1.60.546
      BOF group3.4 ± 2.03.7 ± 2.10.1 ± 0.84.0 ± 2.30.3 ± 1.0
       Resistin (ng/mL)
      Control group6.4 ± 4.86.2 ± 4.4−0.2 ± 2.30.1465.8 ± 3.5−0.5 ± 2.50.015
      BOF group5.6 ± 2.45.9 ± 2.70.4 ± 1.45.9 ± 2.90.6 ± 1.5
       MDA-LDL (U/I)
      Control group124 ± 35121 ± 33−3 ± 330.311119 ± 30−6 ± 370.044
      BOF group126 ± 51126 ± 46−1 ± 43129 ± 404 ± 43
       Pentosidine (ng/mL)
      Control group24 ± 927 ± 103 ± 110.77128 ± 135 ± 140.473
      BOF group30 ± 3031 ± 190 ± 1830 ± 16−2 ± 31
       Urinary L-FABP (μg/g-Cr)
      Control group10.6 ± 20.47.2 ± 9.5−2.7 ± 20.70.8707.6 ± 8.6−2.4 ± 19.50.682
      BOF group6.7 ± 6.47.6 ± 6.90.3 ± 5.69.5 ± 13.82.2 ± 13.0
       Urinary 8-OHdG (μg/g-Cr)
      Control group4.7 ± 2.64.0 ± 1.9−0.6 ± 2.50.0415.1 ± 3.50.4 ± 3.80.171
      BOF group4.5 ± 2.44.9 ± 2.30.3 ± 2.35.9 ± 3.11.3 ± 3.3
      The values are presented as means ± SD. Δ means the change from baseline. LDL, low-density lipoprotein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio; MDA-LDL, malondialdehyde-modified low-density lipoprotein; L-FABP, liver-type fatty acid binding protein; 8-OHdG, 8-hydroxydeoxyguanosine.
      With respect to adipokine and inflammatory markers, while there was no significant change in the adiponectin level between the two groups, the resistin level was significantly elevated in the BOF group compared with the control group after a period of 24 weeks of treatment (Control vs BOF; change from baseline in resistin, −0.5 ± 2.5 vs 0.6 ± 1.5 ng/mL, p = 0.015; Table 4). In addition, the BOF add on therapy significantly increased the malondialdehyde low-density lipoprotein (MDA-LDL) level, an oxidative stress marker, compared with the control group after 24 week treatment (Control vs BOF; change from baseline in MDA-LDL, −6 ± 37 vs 4 ± 43 U/I, p = 0.044; Table 4). Furthermore, the change in the urinary 8-hydroxydeoxyguanosine (8-OHdG) level in the BOF group was significantly higher than the control group after a period of 12 weeks of treatment (Control vs BOF; change from baseline in urinary 8-OHdG, −0.6 ± 2.5 vs 0.3 ± 2.3 μg/g-Cr, p = 0.041; Table 4).

      3.4 Exploratory analysis of contributing factors to change in ambulatory short-term BP variability

      To identify the factors affecting the beneficial change in ambulatory BP variability, we performed multivariate linear regression analysis. In the univariate analysis, BOF usage and the change in serum creatinine were significantly correlated with the change in daytime systolic BP variability (Table 5). Thus, we entered six variables, including age, sex, BOF usage, and the changes in serum creatinine, BMI, and daytime systolic BP level, into the multivariate analysis. The results of the multivariate linear regression analysis in all patients indicated a significant association between the change in daytime systolic BP variability and the BOF usage (Table 5). In addition, the change in serum creatinine was also significantly associated with the change in daytime systolic BP variability.
      Table 5Univariate and multivariate linear regression analysis of the change in daytime systolic BP variability.
      VariablesUnivariateMultivariate
      ρpβp
      Age−0.0730.502−0.0940.373
      Sex0.0560.606−0.0110.921
      BOF add-on therapy group−0.2960.006−0.2980.008
      Change in daytime systolic BP level−0.0920.400−0.1050.334
      Change in BMI0.0880.4240.0620.572
      Change in HbA1c0.0350.746
      Change in serum creatinine−0.2750.010−0.2440.022
      Change in resistin−0.1490.180
      Change in MDA-LDL0.1410.204
      Change in urinary 8-OHdG0.0670.545
      R2 = 0.185
      BP, blood pressure; BMI, body mass index; MDA-LDL, malondialdehyde-modified low-density lipoprotein; 8-OHdG, 8-hydroxydeoxyguanosine.

      3.5 Tolerability

      While there were no adverse events reported in the control group, 3 patients in the BOF group experienced minor adverse events (gastric irritation, constipation, and elevation of serum hepatic enzyme level). No electrolyte abnormality was observed in any of the patients during the active treatment period.

      4. Discussion

      This is the first report, to the best of our knowledge, suggesting that integrative medicine which is defined as a combination therapy of oriental medicine and western medicine (in this case, BOF add-on therapy) is able to exert greater beneficial effects than conventional western therapy alone, based on “out-of-clinic” ambulatory BP profile (i.e. ambulatory BP variability) in hypertensive patients with obesity (Table 2). In the present study, it was demonstrated that the BOF add-on therapy, compared with the conventional therapy, significantly improved short-term BP variability on ambulatory BP monitoring (Table 2), in addition to an anti-obesity effect (reduction in both body weight and BMI) (Table 3). Furthermore, on multivariate analysis, BOF usage was independently associated with the improvement in ambulatory BP variability, in spite of there being no significant relationship to the changes in the BP level or BMI (Table 5). These results suggest that, in obesity-related hypertension, BOF may exert a beneficial effect on short-term BP variability that is independent of the reductions in body weight and/or average BP level.
      Previous studies have shown that the average BP level is the primary BP-related risk factor for CVD and an appropriate BP reduction is essential to both prevent target organ damage and reduce cardiovascular mortality in cases of hypertension [
      • Ninomiya T.
      • Perkovic V.
      • Turnbull F.
      • et al.
      Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials.
      ]. With respect to direct BP lowering capacity of BOF, since the medication status of the antihypertensive agents used was comparable in the two treatment groups during the entire treatment period and antihypertensive agents were increased similarly in both groups to achieve the target clinic BP level (Supplemental Table 2), the direct effect of BOF on average BP lowering may be weak.
      On the other hand, accumulating evidence has indicated that the adverse cardiovascular consequences of high BP not only depend on absolute BP values, but also on BP variability in the short- and long-term [
      • Parati G.
      • Ochoa J.E.
      • Bilo G.
      Blood pressure variability, cardiovascular risk, and risk for renal disease progression.
      ]. Indeed, observational studies have demonstrated that an increased short-term BP variability estimated by ambulatory BP monitoring is closely associated with the development, progression and severity of cardiac, vascular and renal organ damage [
      • Shintani Y.
      • Kikuya M.
      • Hara A.
      • et al.
      Ambulatory blood pressure, blood pressure variability and the prevalence of carotid artery alteration: the Ohasama study.
      ,
      • Tatasciore A.
      • Zimarino M.
      • Tommasi R.
      • et al.
      Increased short-term blood pressure variability is associated with early left ventricular systolic dysfunction in newly diagnosed untreated hypertensive patients.
      ,
      • Sander D.
      • Kukla C.
      • Klingelhofer J.
      • et al.
      Relationship between circadian blood pressure patterns and progression of early carotid atherosclerosis: a 3-year follow-up study.
      ,
      • Sega R.
      • Corrao G.
      • Bombelli M.
      • et al.
      Blood pressure variability and organ damage in a general population: results from the PAMELA study (Pressioni Arteriose Monitorate E Loro Associazioni).
      ,
      • Tatasciore A.
      • Renda G.
      • Zimarino M.
      • et al.
      Awake systolic blood pressure variability correlates with target-organ damage in hypertensive subjects.
      ,
      • Kotsis V.
      • Stabouli S.
      • Karafillis I.
      • et al.
      Arterial stiffness and 24 h ambulatory blood pressure monitoring in young healthy volunteers: the early vascular ageing Aristotle University Thessaloniki Study (EVA-ARIS Study).
      ,
      • Manios E.
      • Stamatelopoulos K.
      • Tsivgoulis G.
      • et al.
      Time rate of blood pressure variation: a new factor associated with coronary atherosclerosis.
      ]. The enhanced short-term BP variability was also shown to be associated with an increased risk of CVD and mortality independently adding to CVD risk, over and above the contribution of elevated mean BP levels [
      • Kikuya M.
      • Hozawa A.
      • Ohokubo T.
      • et al.
      Prognostic significance of blood pressure and heart rate variabilities: the Ohasama study.
      ,
      • Pringle E.
      • Phillips C.
      • Thijs L.
      • et al.
      Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly hypertensive population.
      ,
      • Mancia G.
      • Bombelli M.
      • Facchetti R.
      • et al.
      Long-term prognostic value of blood pressure variability in the general population: results of the Pressioni Arteriose Monitorate e Loro Associazioni Study.
      ]. Although the relative importance of short-term BP variability on ambulatory BP monitoring as an independent prognostic factor of CVD and mortality is still controversial [
      • Parati G.
      • Ochoa J.E.
      • Lombardi C.
      • et al.
      Assessment and management of blood-pressure variability.
      ,
      • Pierdomenico S.D.
      • Di Nicola M.
      • Esposito A.L.
      • et al.
      Prognostic value of different indices of blood pressure variability in hypertensive patients.
      ,
      • Hansen T.W.
      • Thijs L.
      • Li Y.
      • et al.
      Prognostic value of reading-to-reading blood pressure variability over 24 hours in 8938 subjects from 11 populations.
      ], a recent longitudinal study reported that even small increase in short-term BP variability is significantly associated with enhanced risk of CVD and mortality in 7112 hypertensive patients [
      • Palatini P.
      • Reboldi G.
      • Beilin L.J.
      • et al.
      Added predictive value of night-time blood pressure variability for cardiovascular events and mortality: the Ambulatory Blood Pressure-International Study.
      ]. From these results of accumulated evidence we would like to consider that antihypertensive treatment should target improvements in short-term BP variability on ambulatory BP monitoring, in addition to reducing absolute BP levels, in order to achieve the highest cardiovascular protection in hypertensive patients, and BOF may be one of possible candidates to improve short-term BP variability in hypertension with obesity.
      With respect to the mechanism of BOF-mediated improvement in short-term BP variability, it is widely reported that obesity is one of the contributing factors to increased short-term BP variability [
      • Imai Y.
      • Aihara A.
      • Ohkubo T.
      • et al.
      Factors that affect blood pressure variability. A community-based study in Ohasama, Japan.
      ] and it is also reported that reduction in body weight associated with an improvement in BP profile in obese patients [
      • Horvath K.
      • Jeitler K.
      • Siering U.
      • et al.
      Long-term effects of weight-reducing interventions in hypertensive patients: systematic review and meta-analysis.
      ,
      • Goodpaster B.H.
      • Delany J.P.
      • Otto A.D.
      • et al.
      Effects of diet and physical activity interventions on weight loss and cardiometabolic risk factors in severely obese adults: a randomized trial.
      ]. Therefore, the anti-obesity effects (reduction in body weight and BMI) by the BOF add-on therapy may have contributed to the improvement in ambulatory short-term BP variability in the present study. However, in the present study there was no significant relationship between the reduction in BMI and the improvement in short-term BP variability on univariate analysis (Table 5). Therefore, it is also possible that BOF further improved the effect on short-term BP variability, which is not mediated by its anti-obesity effect. Collectively, the BOF-mediated effect on ambulatory BP variability, rather than a direct BP lowering effect, appears to improve the “quality” of BP management of obesity-related hypertension.
      In the present study, the BOF add-on therapy accelerated the body weight reduction (Table 3) and exerted a more favorable effect on glucose metabolism than the conventional therapy group (Table 4). These results are consistent with a previous clinical study demonstrating that treatment with BOF was effective in decreasing visceral fat and in improving glucose metabolism in obese Japanese women [
      • Hioki C.
      • Yoshimoto K.
      • Yoshida T.
      Efficacy of bofu-tsusho-san, an oriental herbal medicine, in obese Japanese women with impaired glucose tolerance.
      ]. Since BOF add-on therapy reduced HbA1c level (Table 4) but exerted no evident effects on serum insulin level and HOMA-IR (data not shown), further study is needed to examine beneficial effects of BOF on insulin sensitivity and related parameters such as leptin in obesity hypertension.
      On the other hand, there were several unexpected findings concerning the BOF-mediated changes in inflammatory adipokines and markers of oxidative stress. The inflammatory adipokine resistin and the oxidative stress markers MDA-LDL and urinary 8-OHdG have been reported to be associated with cardiovascular risk factors, including obesity and hypertension [
      • Menzaghi C.
      • Bacci S.
      • Salvemini L.
      • et al.
      Serum resistin, cardiovascular disease and all-cause mortality in patients with type 2 diabetes.
      ,
      • Rosello-Lleti E.
      • de Burgos F.G.
      • Morillas P.
      • et al.
      Impact of cardiovascular risk factors and inflammatory status on urinary 8-OHdG in essential hypertension.
      ,
      • Lopes-Virella M.F.
      • Hunt K.J.
      • Baker N.L.
      • et al.
      The levels of MDA-LDL in circulating immune complexes predict myocardial infarction in the VADT study.
      ,
      • Tsimikas S.
      • Willeit P.
      • Willeit J.
      • et al.
      Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events.
      ]. In the present study, resistin, MDA-LDL, and urinary 8-OHdG in the BOF add-on therapy group were significantly elevated compared with the conventional therapy group (Table 4), in spite of the efficient reduction in body weight and BMI in the BOF group. However, there are several interesting preceding studies showing that the body weight reduction exerted by dietary therapy and/or exercise guidance resulted in increases in the circulating resistin concentration and urinary 8-OHdG level [
      • Koebnick C.
      • Wagner K.
      • Garcia A.L.
      • et al.
      Increase in serum resistin during weight loss in overweight subjects is related to lipid metabolism.
      ,
      • Elloumi M.
      • Ben Ounis O.
      • Makni E.
      • et al.
      Effect of individualized weight-loss programmes on adiponectin, leptin and resistin levels in obese adolescent boys.
      ,
      • Ahmadi N.
      • Eshaghian S.
      • Huizenga R.
      • et al.
      Effects of intense exercise and moderate caloric restriction on cardiovascular risk factors and inflammation.
      ,
      • Lee K.H.
      • Bartsch H.
      • Nair J.
      • et al.
      Effect of short-term fasting on urinary excretion of primary lipid peroxidation products and on markers of oxidative DNA damage in healthy women.
      ,
      • Mizoue T.
      • Tokunaga S.
      • Kasai H.
      • et al.
      Body mass index and oxidative DNA damage: a longitudinal study.
      ,
      • Yanagawa Y.
      • Morimura T.
      • Tsunekawa K.
      • et al.
      Oxidative stress associated with rapid weight reduction decreases circulating adiponectin concentrations.
      ]. Therefore, the causal relationship between body weight reduction and changes in the inflammatory adipokines and markers of oxidative stress remains to be determined in the pathophysiology of obesity related hypertension.
      The limitations of the present study include the design not being a double-blinded placebo-controlled study. Also, further studies with a longer treatment period are needed to investigate whether the beneficial effects of BOF on ambulatory BP variability would be maintained with continued benefit for the cardiovascular function parameters without serious adverse events. In addition, the R2 level in the multivariate analysis was relatively low (R2 = 0.185) (Table 5) and the mechanism of the beneficial effect of BOF on ambulatory BP variability remains to be determined. Since the improvement in short-term BP variability conferred by BOF add-on therapy on short-term BP is independent of its anti-obesity effect and BP reduction, other factors such as its putative effects on vasoactive substance, endothelial function and/or renal sodium handling would be possible candidates involved [
      • Ohno K.
      • Chung H.J.
      • Maruyama I.
      • et al.
      Bofutsushosan, a traditional Chinese formulation, prevents intimal thickening and vascular smooth muscle cell proliferation induced by balloon endothelial denudation in rats.
      ,
      • Yiannikouris F.
      • Gupte M.
      • Putnam K.
      • et al.
      Adipocyte deficiency of angiotensinogen prevents obesity-induced hypertension in male mice.
      ]. We indeed reported that the BOF-mediated improvement in adipose tissue function by amelioration of adipokine dysregulation as well as the reduction of food intake by the appetite-inhibitory property of BOF through suppression on the ghrelin system contribute to the BP lowering effect and favorable metabolic modulation by BOF in a mouse model of human metabolic disorders with obesity [
      • Azushima K.
      • Tamura K.
      • Wakui H.
      • et al.
      Bofu-tsu-shosan, an oriental herbal medicine, exerts a combinatorial favorable metabolic modulation including antihypertensive effect on a mouse model of human metabolic disorders with visceral obesity.
      ]. Nevertheless, as a major limitation of the present study, the mechanism whereby BOF improved short-term BP variability is still not clear. Therefore, further experimental results and clinical trials that support the hypothesis and elucidate the mechanism whereby BOF improves short-term BP variability in hypertension with obesity.
      Furthermore, the present study did not intend to examine the effects of the individual components of BOF on BP profile in the participants. A recent case report showed that ephedrine, a component of BOF, could induce pulmonary arterial hypertension [
      • Sakurai Y.
      • Tanabe N.
      • Sekine A.
      • et al.
      Spontaneously remitted pulmonary arterial hypertension associated with the herbal medicine “bofutsushosan”.
      ] and it would be possible that BOF treatment may exert the adverse effects caused via the enhanced sympathetic nerve activity by ephedrine. However, no patients in the BOF group reported symptoms related to activation of sympathetic nerve activity, such as palpitation, and changes in BP and HR were comparable in the two groups after the treatment. These results suggest that the clinical dose of BOF may not exert the adverse effects caused by activation of sympathetic nerve due to relatively few contents of ephedrine in BOF. Nevertheless, the target mechanism of oriental herbal formulas at the level of each active ingredient for hypertension is an important issue for the development of antihypertensive drugs based on oriental herbal medicine. Therefore, further basic and clinical studies are warranted to investigate the role of each component of BOF in its clinical efficacy.
      In conclusion, the BOF add-on therapy effectively improved the ambulatory short-term BP variability, concomitantly with its anti-obesity effects. Therefore, the integrative medicine approach used here, employing this oriental herbal medicine, appeared to improve the ambulatory BP variability in obesity related hypertension better than conventional therapy by western medicine alone.

      Conflict of interest

      None declared.

      Acknowledgments

      This study was entirely funded by the Japanese Ministry of Health, Labour and Welfare (Health and Labour Sciences Research grant).

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:

      References

        • Ng M.
        • Fleming T.
        • Robinson M.
        • et al.
        Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013.
        Lancet. 2014; 384: 766-781
        • Landsberg L.
        • Aronne L.J.
        • Beilin L.J.
        • et al.
        Obesity-related hypertension: pathogenesis, cardiovascular risk, and treatment – a position paper of the The Obesity Society and The American Society of Hypertension.
        Obes. (Silver Spring). 2013; 21: 8-24
        • Dietrich M.O.
        • Horvath T.L.
        Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons.
        Nat. Rev. Drug Discov. 2012; 11: 675-691
        • Dixon J.B.
        • le Roux C.W.
        • Rubino F.
        • et al.
        Bariatric surgery for type 2 diabetes.
        Lancet. 2012; 379: 2300-2311
        • Yoshida T.
        • Sakane N.
        • Wakabayashi Y.
        • et al.
        Thermogenic, anti-obesity effects of bofu-tsusho-san in MSG-obese mice.
        Int. J. Obes. Relat. Metab. Disord. 1995; 19: 717-722
        • Ono M.
        • Ogasawara M.
        • Hirose A.
        • et al.
        Bofutsushosan, a Japanese herbal (Kampo) medicine, attenuates progression of nonalcoholic steatohepatitis in mice.
        J. Gastroenterol. 2014; 49: 1065-1073
        • Azushima K.
        • Tamura K.
        • Wakui H.
        • et al.
        Bofu-tsu-shosan, an oriental herbal medicine, exerts a combinatorial favorable metabolic modulation including antihypertensive effect on a mouse model of human metabolic disorders with visceral obesity.
        PLoS One. 2013; 8: e75560
        • Xiong X.
        • Yang X.
        • Liu Y.
        • et al.
        Chinese herbal formulas for treating hypertension in traditional Chinese medicine: perspective of modern science.
        Hypertens. Res. 2013; 36: 570-579
        • Hodgkinson J.
        • Mant J.
        • Martin U.
        • et al.
        Relative effectiveness of clinic and home blood pressure monitoring compared with ambulatory blood pressure monitoring in diagnosis of hypertension: systematic review.
        BMJ. 2011; 342: d3621
        • Mancia G.
        • Parati G.
        Ambulatory blood pressure monitoring and organ damage.
        Hypertension. 2000; 36: 894-900
        • Kikuya M.
        • Hozawa A.
        • Ohokubo T.
        • et al.
        Prognostic significance of blood pressure and heart rate variabilities: the Ohasama study.
        Hypertension. 2000; 36: 901-906
        • Shintani Y.
        • Kikuya M.
        • Hara A.
        • et al.
        Ambulatory blood pressure, blood pressure variability and the prevalence of carotid artery alteration: the Ohasama study.
        J. Hypertens. 2007; 25: 1704-1710
        • Tatasciore A.
        • Zimarino M.
        • Tommasi R.
        • et al.
        Increased short-term blood pressure variability is associated with early left ventricular systolic dysfunction in newly diagnosed untreated hypertensive patients.
        J. Hypertens. 2013; 31: 1653-1661
        • Parati G.
        • Ochoa J.E.
        • Lombardi C.
        • et al.
        Assessment and management of blood-pressure variability.
        Nat. Rev. Cardiol. 2013; 10: 143-155
        • Shimamoto K.
        • Ando K.
        • Fujita T.
        • et al.
        The Japanese Society of hypertension guidelines for the management of hypertension (JSH 2014).
        Hypertens. Res. 2014; 37: 253-387
        • Kanaoka T.
        • Tamura K.
        • Moriya T.
        • et al.
        Effects of multiple factorial intervention on ambulatory BP profile and renal function in hypertensive type 2 diabetic patients with overt nephropathy – a pilot study.
        Clin. Exp. Hypertens. 2011; 33: 255-263
        • Kanaoka T.
        • Tamura K.
        • Ohsawa M.
        • et al.
        Effects of aliskiren-based therapy on ambulatory blood pressure profile, central hemodynamics, and arterial stiffness in nondiabetic mild to moderate hypertensive patients.
        J. Clin. Hypertens. (Greenwich). 2012; 14: 522-529
        • Kanaoka T.
        • Tamura K.
        • Wakui H.
        • et al.
        L/N-type calcium channel blocker cilnidipine added to renin-angiotensin inhibition improves ambulatory blood pressure profile and suppresses cardiac hypertrophy in hypertension with chronic kidney disease.
        Int. J. Mol. Sci. 2013; 14: 16866-16881
        • Yanagi M.
        • Tamura K.
        • Fujikawa T.
        • et al.
        The angiotensin II type 1 receptor blocker olmesartan preferentially improves nocturnal hypertension and proteinuria in chronic kidney disease.
        Hypertens. Res. 2013; 36: 262-269
        • Azushima K.
        • Uneda K.
        • Tamura K.
        • et al.
        Effects of single pill-based combination therapy of amlodipine and atorvastatin on within-visit blood pressure variability and parameters of renal and vascular function in hypertensive patients with chronic kidney disease.
        Biomed. Res. Int. 2014; 2014: 437087
        • Yamashina A.
        • Tomiyama H.
        • Takeda K.
        • et al.
        Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement.
        Hypertens. Res. 2002; 25: 359-364
        • Ninomiya T.
        • Perkovic V.
        • Turnbull F.
        • et al.
        Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials.
        BMJ. 2013; 347: f5680
        • Parati G.
        • Ochoa J.E.
        • Bilo G.
        Blood pressure variability, cardiovascular risk, and risk for renal disease progression.
        Curr. Hypertens. Rep. 2012; 14: 421-431
        • Sander D.
        • Kukla C.
        • Klingelhofer J.
        • et al.
        Relationship between circadian blood pressure patterns and progression of early carotid atherosclerosis: a 3-year follow-up study.
        Circulation. 2000; 102: 1536-1541
        • Sega R.
        • Corrao G.
        • Bombelli M.
        • et al.
        Blood pressure variability and organ damage in a general population: results from the PAMELA study (Pressioni Arteriose Monitorate E Loro Associazioni).
        Hypertension. 2002; 39: 710-714
        • Tatasciore A.
        • Renda G.
        • Zimarino M.
        • et al.
        Awake systolic blood pressure variability correlates with target-organ damage in hypertensive subjects.
        Hypertension. 2007; 50: 325-332
        • Kotsis V.
        • Stabouli S.
        • Karafillis I.
        • et al.
        Arterial stiffness and 24 h ambulatory blood pressure monitoring in young healthy volunteers: the early vascular ageing Aristotle University Thessaloniki Study (EVA-ARIS Study).
        Atherosclerosis. 2011; 219: 194-199
        • Manios E.
        • Stamatelopoulos K.
        • Tsivgoulis G.
        • et al.
        Time rate of blood pressure variation: a new factor associated with coronary atherosclerosis.
        J. Hypertens. 2011; 29: 1109-1114
        • Pringle E.
        • Phillips C.
        • Thijs L.
        • et al.
        Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly hypertensive population.
        J. Hypertens. 2003; 21: 2251-2257
        • Mancia G.
        • Bombelli M.
        • Facchetti R.
        • et al.
        Long-term prognostic value of blood pressure variability in the general population: results of the Pressioni Arteriose Monitorate e Loro Associazioni Study.
        Hypertension. 2007; 49: 1265-1270
        • Pierdomenico S.D.
        • Di Nicola M.
        • Esposito A.L.
        • et al.
        Prognostic value of different indices of blood pressure variability in hypertensive patients.
        Am. J. Hypertens. 2009; 22: 842-847
        • Hansen T.W.
        • Thijs L.
        • Li Y.
        • et al.
        Prognostic value of reading-to-reading blood pressure variability over 24 hours in 8938 subjects from 11 populations.
        Hypertension. 2010; 55: 1049-1057
        • Palatini P.
        • Reboldi G.
        • Beilin L.J.
        • et al.
        Added predictive value of night-time blood pressure variability for cardiovascular events and mortality: the Ambulatory Blood Pressure-International Study.
        Hypertension. 2014; 64: 487-493
        • Imai Y.
        • Aihara A.
        • Ohkubo T.
        • et al.
        Factors that affect blood pressure variability. A community-based study in Ohasama, Japan.
        Am. J. Hypertens. 1997; 10: 1281-1289
        • Horvath K.
        • Jeitler K.
        • Siering U.
        • et al.
        Long-term effects of weight-reducing interventions in hypertensive patients: systematic review and meta-analysis.
        Arch. Intern. Med. 2008; 168: 571-580
        • Goodpaster B.H.
        • Delany J.P.
        • Otto A.D.
        • et al.
        Effects of diet and physical activity interventions on weight loss and cardiometabolic risk factors in severely obese adults: a randomized trial.
        JAMA. 2010; 304: 1795-1802
        • Hioki C.
        • Yoshimoto K.
        • Yoshida T.
        Efficacy of bofu-tsusho-san, an oriental herbal medicine, in obese Japanese women with impaired glucose tolerance.
        Clin. Exp. Pharmacol. Physiol. 2004; 31: 614-619
        • Menzaghi C.
        • Bacci S.
        • Salvemini L.
        • et al.
        Serum resistin, cardiovascular disease and all-cause mortality in patients with type 2 diabetes.
        PLoS One. 2013; 8: e64729
        • Rosello-Lleti E.
        • de Burgos F.G.
        • Morillas P.
        • et al.
        Impact of cardiovascular risk factors and inflammatory status on urinary 8-OHdG in essential hypertension.
        Am. J. Hypertens. 2012; 25: 236-242
        • Lopes-Virella M.F.
        • Hunt K.J.
        • Baker N.L.
        • et al.
        The levels of MDA-LDL in circulating immune complexes predict myocardial infarction in the VADT study.
        Atherosclerosis. 2012; 224: 526-531
        • Tsimikas S.
        • Willeit P.
        • Willeit J.
        • et al.
        Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events.
        J. Am. Coll. Cardiol. 2012; 60: 2218-2229
        • Koebnick C.
        • Wagner K.
        • Garcia A.L.
        • et al.
        Increase in serum resistin during weight loss in overweight subjects is related to lipid metabolism.
        Int. J. Obes. (Lond.). 2006; 30: 1097-1103
        • Elloumi M.
        • Ben Ounis O.
        • Makni E.
        • et al.
        Effect of individualized weight-loss programmes on adiponectin, leptin and resistin levels in obese adolescent boys.
        Acta Paediatr. 2009; 98: 1487-1493
        • Ahmadi N.
        • Eshaghian S.
        • Huizenga R.
        • et al.
        Effects of intense exercise and moderate caloric restriction on cardiovascular risk factors and inflammation.
        Am. J. Med. 2011; 124: 978-982
        • Lee K.H.
        • Bartsch H.
        • Nair J.
        • et al.
        Effect of short-term fasting on urinary excretion of primary lipid peroxidation products and on markers of oxidative DNA damage in healthy women.
        Carcinogenesis. 2006; 27: 1398-1403
        • Mizoue T.
        • Tokunaga S.
        • Kasai H.
        • et al.
        Body mass index and oxidative DNA damage: a longitudinal study.
        Cancer Sci. 2007; 98: 1254-1258
        • Yanagawa Y.
        • Morimura T.
        • Tsunekawa K.
        • et al.
        Oxidative stress associated with rapid weight reduction decreases circulating adiponectin concentrations.
        Endocr. J. 2010; 57: 339-345
        • Ohno K.
        • Chung H.J.
        • Maruyama I.
        • et al.
        Bofutsushosan, a traditional Chinese formulation, prevents intimal thickening and vascular smooth muscle cell proliferation induced by balloon endothelial denudation in rats.
        Biol. Pharm. Bull. 2005; 28: 2162-2165
        • Yiannikouris F.
        • Gupte M.
        • Putnam K.
        • et al.
        Adipocyte deficiency of angiotensinogen prevents obesity-induced hypertension in male mice.
        Hypertension. 2012; 60: 1524-1530
        • Sakurai Y.
        • Tanabe N.
        • Sekine A.
        • et al.
        Spontaneously remitted pulmonary arterial hypertension associated with the herbal medicine “bofutsushosan”.
        Intern. Med. 2013; 52: 1499-1502