Effect of Bezafibrate on Office, Home and Ambulatory Blood Pressure In

Home , Bezafibrate, Clofibrate

ORIGINAL ARTICLE Effect of bezaﬁbrate on ofﬁce, home and ambulatory blood pressure in hypertensive patients with dyslipidemia

Y Ohta, Y Kawano, Y Iwashima, S Hayashi, F Yoshihara and S Nakamura

It has been suggested that fibrates, lipid-lowering agents with a peroxisome proliferator-activated receptor-a agonistic property, lower blood pressure (BP) in some experimental models of hypertension. However, the effect of fibrates on BP in humans has been inconsistent, and there are few studies using home or ambulatory BP monitoring. We investigated the effects of bezafibrate on office, home and ambulatory BP in hypertensive patients with dyslipidemia. Thirty-two essential hypertensive patients with dyslipidemia (6 men and 26 women, mean age 65±8 years old) were assigned to a control period and a bezafibrate period (200 mg twice daily) for 8 weeks each in a randomized crossover manner. Bezafibrate significantly reduced serum triglyceride, total and low- density lipoprotein-cholesterol, blood glucose, plasma insulin, the homeostasis model assessment ratio and increased high-density lipoprotein-cholesterol. Compared with the control period, changes in office, home and 24-h BP with bezafibrate were À 0.7±2.1/ À 1.6±1.2 mm Hg, þ 0.9±1.0/ À 0.5±0.6 and þ 0.8±1.4/ À 0.6±0.9 mm Hg, respectively. None of these differences in BP was significant. In conclusion, bezafibrate improved lipid metabolism and insulin sensitivity but did not affect office, home or ambulatory BP in hypertensive patients with dyslipidemia. Fibrates do not appear to lower BP in patients with essential hypertension.

Journal of Human Hypertension (2013) 27, 417–420; doi:10.1038/jhh.2012.64; published online 20 December 2012 Keywords: Bezaﬁbrate; dyslipidemia; home blood pressure; ambulatory blood pressure monitoring; insulin sensitivity

INTRODUCTION included 32 essential hypertensive patients, 26 women and 6 men, mean Hypertension and dyslipidemia are frequently associated and their age 65±8 years, who had dyslipidemia. Hypertension was considered to combination additionally increases cardiovascular risk.1–3 be present if the patients showed systolic BP (SBP) X140 mm Hg and/or Hypertension and dyslipidemia, especially hypertriglyceridemia are diastolic BP X90 mm Hg, or if they were on antihypertensive medication. X À 1 also closely linked to obesity, insulin resistance, impaired glucose Dyslipidemia was defined as serum total cholesterol 220 mg dl and/or fasting serum triglyceride X150 mg dl À 1. This study was performed in tolerance and metabolic syndrome.2,4,5 Fibrates have been widely accordance with the institutional guideline and approved by the ethical used in the treatment of dyslipidemia. They act as PPAR (peroxisome committee. Written informed consent was obtained from each patient. proliferator-activated receptor)-a agonists, reduce serum triglyceride The subjects were randomly assigned to an 8-week bezafibrate period and LDL (low-density lipoprotein)-cholesterol and increase the level (200 mg twice a day) and an 8-week control period in a crossover design. Office of high-density lipoprotein (HDL)-cholesterol.6,7 Fibrates have also BP and 24-h ambulatory BP were measured at the end of the control and been shown to improve insulin sensitivity.6–8 bezafibrate periods. Home BP was measured throughout the study protocol. At It has been suggested that fibrates lower blood pressure (BP) in the end of each period, fasting blood samples were obtained to determine several experimental models of hypertension.9–11 However, results of lipids, glucose and insulin. The majority of patients (n ¼ 25) were being treated clinical studies regarding the effect of fibrates on BP were with antihypertensive drugs, but no patients were treated with lipid-lowering inconsistent,12–15 and there are few studies using home or agents before this study. Antihypertensive therapy was continued without any alterations throughout the study protocol. ambulatory BP monitoring in the assessment of changes in BP. It is Office BP was measured twice with a mercury sphygmomanometer by a well documented that home BP and ambulatory BP are superior to doctor while the patients were quietly seated, and the averaged values 16,17 office BP in the diagnosis and treatment of hypertension. Home were used for analysis. Home BP was measured in the sitting position by BP measurement and ambulatory BP monitoring can detect small the patients three times in the early morning and in the late evening, using changes in BP caused by pharmacological and non-pharmacological semiautomatic devices with the oscillometric method (HEM-757, Omron interventions in a limited number of subjects.18–20 In the present Corp., Kyoto, Japan). The average values of home BP during the last 7 days study, we examined the effects of bezafibrate on office, home and of each period (42 records) were used for statistical analysis. Ambulatory 24-h BP, as well as lipid and glucose metabolism, in hypertensive BP was monitored oscillometrically every 30 min for 25–26 h using an patients with dyslipidemia. automatic device (TM-2421; A&D Co. Ltd., Tokyo, Japan). The accuracy and performance of this device have been demonstrated previously.21 The same recorder was used in each subject to avoid errors due to differences in equipment. After discarding records during the first 1 h, the average SUBJECTS AND METHODS values of 24-h records were used for analysis. The homeostasis model Participants were recruited from the Hypertension Clinic of the National assessment ratio (HOMA-R), an index of insulin resistance, was calculated Cerebral and Cardiovascular Center, Osaka, Japan. The study subjects as fasting plasma glucose (mg dl À 1) Â fasting insulin (mUmlÀ 1)/405.22

Division of Hypertension and Nephrology, National Cerebral and Cardiovascular Center, Osaka, Japan. Correspondence: Dr Y Ohta, Division of Hypertension and Nephrology, National Cerebral and Cardiovascular Center, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan. E-mail: [email protected] Received 3 September 2012; revised 24 October 2012; accepted 19 November 2012; published online 20 December 2012 Effect of Bezafibrate on blood pressure Y Ohta et al 418 Values are presented as the mean±s.d. The Student’s paired t-test was þ 0.9±1.0/ À 0.5±0.6 mm Hg and þ 0.8±1.4/ À 0.6±0.9 mm Hg, used to compare the two groups of data. P-values o0.05 were considered respectively. None of these changes was statistically significant. statistically significant. Analyses were performed using Stat View software In univariate analyses, the changes in office, home and 24-h BP (Abacus Concepts Inc., Berkeley, CA, USA). with bezafibrate inversely correlated with the baseline levels of each corresponding BP (data not shown). There were no significant relationships between the changes in office, home or RESULTS 24-h BP with bezafibrate treatment and the changes in lipid and Clinical characteristics and biochemical parameters of the subjects glucose metabolism parameters. in the control and bezafibrate periods are shown in Table 1. Treatment with bezafibrate significantly reduced levels of serum total cholesterol, triglyceride and LDL-cholesterol, and significantly DISCUSSION increased serum HDL-cholesterol (Table 1, Figure 1). Bezafibrate In the present study, we demonstrated that administration of also significantly reduced blood glucose, plasma insulin and bezafibrate for 8 weeks improved lipid metabolism and insulin HOMA-R, but it did not affect serum HbA1c and decreased sensitivity in hypertensive patients with dyslipidemia. However, estimated glomerular filtration rate (Table 1, Figure 2). bezafibrate did not affect any of the office, home or 24-h BP levels The levels of office, home and 24-h BP were similar between the in these patients. bezafibrate and control periods (Table 2). Changes in office, home Hypertriglyceridemia, part of a complex metabolic disorder, is and 24-h BP with bezafibrate were À 0.7±2.1/ À 1.6±1.2 mm Hg, strongly associated with all atherogenic factors such as dis- turbances in coagulation and fibrinolysis, the occurrence of hypertension, and the presence of both hyperinsulinemia and 23 Table 1. Clinical characteristics and biochemical parameters in the elevated free fatty acid levels. Many previous studies have control and bezafibrate periods (N ¼ 32) shown that serum triglyceride levels are independently predictive of CVD (cardiovascular disease).24–26 A low serum HDL-cholesterol 27 Control Bezafibrate level is associated with a high risk of atherosclerosis. The combination of low HDL-cholesterol and high triglyceride has Age (years) 65±8 been shown to be a stronger risk factor for CVD,3,28 and to be Average number of 2.0±1.3 29 antihypertensive drugs associated with hyperinsulinemia. Regarding the treatment of Body weight (kg) 59.5±9.1 59.3±9.1 dyslipidemia, reducing triglyceride with bezafibrate was Body mass index (kg m À 2) 24.8±3.4 24.8±3.4 suggested to be important for the prevention of CVD.30 Because Serum total cholesterol 243±27 211±24** À 1 bezafibrate has been reported to delay the progression of (mg dl ) 31 Serum triglyceride (mg dl À 1) 157±73 81±35*** atherosclerotic lesions, fibrates seem to play a prominent role Serum HDL-cholesterol 52±12 63±13** in the management of dyslipidemia. (mg dl À 1) In the present study, bezafibrate significantly reduced blood Serum LDL-cholesterol 159±30 131±24** glucose, plasma insulin and HOMA-R, indicating an improvement (mg dl À 1) Blood glucose (mg dl À 1)97±894±8* in insulin resistance. It has been suggested that fibrates not only Hemoglobin A1c (%) 5.5±0.3 5.6±0.4 reduce lipid levels by increasing catabolism of very low-density Plasma insulin (mUmlÀ 1) 6.5±3.6 4.8±2.9** lipoprotein,32 but also improve insulin sensitivity and fatty acid HOMA-R 1.6±0.2 1.1±0.1** composition of skeletal muscle triglycerides by reducing eGFR (ml per minute per 69.7±16.7 65.7±17.5** 33,34 1.73 m2) intramuscular lipid content. Fibrates may improve metabolic disorders by regulation of insulin concentration, regulation of Abbreviations: eGFR, estimated glomerular filtration rate; HDL, high- plasma and cell membrane lipid composition and activation of density lipoprotein; HOMA-R, homeostasis model assessment insulin PPAR-related genes and proteins in many organs and tissues. resistance; LDL, low-density lipoprotein. Values are expressed as Although dyslipidemia often coexists with hypertension, it has mean±s.d. *P 0.05, **P 0.01, ***P 0.001 vs control period. o o o not been recognized as a major determinant of BP. However, there

250 200 ** 200 150 150 100 100 *** (mg/dl) (mg/dl) 50 50

0 0

200 100

150 75 ** ** 100 50 (mg/dl) (mg/dl) 50 25

0 0 Control Bezafibrate Control Bezafibrate Figure 1. Serum lipids in the control and bezaﬁbrate periods. (a) Total cholesterol, (b) triglyceride, (c) LDL-cholesterol and (d) HDL-cholesterol. **Po0.01, ***Po0.001 vs control period.

Journal of Human Hypertension (2013) 417 – 420 & 2013 Macmillan Publishers Limited Effect of Bezaﬁbrate on blood pressure Y Ohta et al 419 100 6 * 5 75 4 50 3 (%)

(mg/dl) 2 25 1 0 0

7 2.0 6 5 ** 1.5 ** 4 1.0 3 (μU/ml) 2 0.5 1 0 0 Control Bezafibrate Control Bezafibrate Figure 2. Parameters related to glucose metabolism in the control and bezaﬁbrate periods. (a) Blood glucose, (b) hemoglobin A1c, (c) plasma insulin and (d) HOMA-R. *Po0.05, **Po0.01 vs control period.

pharmacological and non-pharmacological interventions in a limited Table 2. Office, home and 24-h ambulatory blood pressure levels in number of subjects.18–20 Therefore, our study does not support the the control and bezafibrate periods (N 32) ¼ concept that fibrates exert a clinically relevant antihypertensive effect Control Bezafibrate on hypertensive patients with dyslipidemia. Earlier studies that showed reductions in BP with fibrates used only casual BP 13,37 Office SBP (mm Hg) 149.4±11.8 148.8±11.8 measurements, and the two studies were not controlled. In the Office DBP (mm Hg) 89.8±7.7 88.1±8.4 study using ambulatory BP monitoring, fenofibrate somewhat Home SBP (mm Hg) 132.3±9.0 133.2±8.4 elevated 24-h systolic BP in healthy subjects and did not affect the Home DBP (mm Hg) 81.1±7.1 80.6±6.8 glucocorticoid-induced BP elevation.15 24-h SBP (mm Hg) 132.0±9.3 132.8±6.8 Hyperinsulinemia is thought to elevate BP through sodium ± ± 24-h DBP (mm Hg) 80.7 7.8 80.2 7.4 retention, activation of the sympathetic nervous system, endothelial 2,4 Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. dysfunction and vascular remodeling. However, insulin also has Values are expressed as mean±s.d. vasodilatory properties and its effects on BP may be complex. In the present study, bezafibrate significantly reduced serum insulin and improved insulin sensitivity, but did not affect BP in hypertensive patients with dyslipidemia, although average baseline levels of insulin is some evidence suggesting the role of dyslipidemia in the and HOMA were not elevated. These results are in accordance with regulation of BP and the development of hypertension.35,36 It our previous study in which BP in overweight subjects was reduced by has been shown that fibrates reduce BP in several models weight reduction with a hypocaloric diet, but not by treatment with of experimental hypertension such as Dahl salt-sensitive the insulin-sensitizing agent troglitazone.20 rats, spontaneously hypertensive rats and fructose-induced Our study may have several limitations. First, we did not insert a hypertensive rats.9–11 There are also several clinical studies that washout period between the control and bezafibrate periods. showed significant reductions in BP with fibrates in patients with However, the effect of treatment was likely to disappear after 2 hypertriglyceridemia,12 hypertension and hypertriglyceridemia13 months because levels of serum lipids, glucose and insulin were and metabolic syndrome.37 Several mechanisms for the reduction significantly different between the two periods. Second, our study in BP with fibrates have been considered, including improved was not double-blinded and was carried out without administra- insulin sensitivity, increased renal blood flow and reduced renal tion of a placebo in the control period. However, the present study vascular resistance, and improved endothelium-dependent nitric was undertaken in a randomized crossover manner, and we used oxide-mediated vasodilatation.9–13,38 However, the results of home and ambulatory BP measurements, which can avoid the clinical studies examining the effect of fibrates on BP have been placebo effect and observer bias. These methods are considered inconsistent. In some studies, clofibrate or fenofibrate did not to minimize the weakness of the study design. Third, the number lower BP in patients with type 2 diabetes mellitus.14,39 of study subjects was not large, although earlier studies showing In the present study, bezafibrate did not affect any of the office, positive effect of fibrates on BP12,13 employed even fewer subjects home or 24-h BP levels in hypertensive patients with dyslipidemia. than our study. Finally, the majority of the study subjects were To our knowledge, the effects of fibrates on home BP have not treated with antihypertensive drugs, and the levels of BP, lipids, been investigated, and there is only one study that examined glucose and insulin were not very high. It is possible that the effect of bezafibrate on 24-h ambulatory BP.15 Home and bezafibrate exerts an antihypertensive effect if these levels are ambulatory BP are considered to have clinical values greater than remarkably elevated in study subjects. However, in the present that of clinic BP. It has been shown that these BP measures study average office BP in the control period was about 150/ correlated more closely with hypertensive target organ damage 90 mm Hg, which appears to be high enough to investigate the and cardiovascular prognosis than clinic BP.16,17,40,41 Home BP and effect of intervention on BP. ambulatory BP are not influenced by the placebo effect or In conclusion, treatment with bezafibrate significantly improved observer bias, and can detect small changes in BP caused by the serum lipid profile and insulin sensitivity, but did not affect

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Journal of Human Hypertension (2013) 417 – 420 & 2013 Macmillan Publishers Limited