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Clinical Chemistry 52: 2036-2042, 2006. First published September 21, 2006; 10.1373/clinchem.2006.074724
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(Clinical Chemistry. 2006;52:2036-2042.)
© 2006 American Association for Clinical Chemistry, Inc.

Lipids, Lipoproteins, and Cardiovascular Risk Factors

Inhibitory Effects of Micronized Fenofibrate on Carotid Atherosclerosis in Patients with Essential Hypertension

Shiming Zhu1,2, Guohai Su2 and Qing H. Meng1,a

1 Department of Pathology and Laboratory Medicine, Royal University Hospital, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
2 Department of Medicine, Clinical Medical College of Shandong University, Jinan, China.

aAddress correspondence to this author at: Department of Pathology and Laboratory Medicine, Room 4917, Royal University Hospital, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK, S7N 0W8 Canada. Fax 306-655-2193; e-mail qing.meng{at}usask.ca.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: The coexistence of hypertension and dyslipidemia synergistically increases the risk of cardiovascular events. We investigated the effect of the lipid-lowering agent micronized fenofibrate on inhibition of carotid atherosclerosis in patients with essential hypertension and mild hyperlipidemia.

Methods: We measured serum lipid profiles and inflammatory markers on chemistry or immune analyzers and common or internal carotid intima-media thickness (IMT) and diameter (D) by ultrasonography.

Results: Patients receiving micronized fenofibrate for 24 months in addition to antihypertensive treatment had decreased concentrations of total cholesterol, LDL-cholesterol, triglyceride, apolipoprotein B100, oxidized LDL, high-sensitivity C-reactive protein, P-selectin, and cytokines. These patients had increased concentrations of HDL-cholesterol, apolipoprotein A-I, and nitric oxide. Common carotid artery IMT (CCAIMT) and internal carotid artery IMT (ICAIMT) remained unchanged during the 24-month intervention. Moreover, the mean CCAIMT/D ratio and ICAIMT/D ratio were significantly decreased in the fenofibrate intervention group. In contrast, CCAIMT/D and ICAIMT/D ratios were increased in the control group. The incidence rates of carotid artery plaque formation and stroke in the fenofibrate intervention group were significantly lower than those in the control group.

Conclusion: The combination of antihypertensive agents with micronized fenofibrate can effectively prevent the progression of carotid atherosclerosis and reduce the incidence of stroke in patients with essential hypertension.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Increased blood pressure is associated with the development of atherosclerosis and atherosclerosis-associated cardiovascular disease (1), with approximately two thirds of strokes and one half of coronary heart disease cases worldwide occurring in patients with high blood pressure (2). Essential hypertension is one of the most prevalent health problems worldwide and is known to be an important risk factor for cardiovascular and cerebrovascular diseases (3). Patients with essential hypertension have increased cardio-cerebrovascular morbidity and mortality (4)(5). Hyperlipidemia is a well-established risk factor for atherosclerosis and cardiovascular disease, accounting for 18% of cerebrovascular disease and 56% of coronary heart disease worldwide (2). The coexistence of hypertension and dyslipidemia synergistically increases the risk of coronary heart disease and cerebrovascular disease (6). Carotid artery intima-media thickness (IMT)1 is an indicator of generalized atherosclerosis and the risk of coronary and cerebrovascular events (7)(8)(9). Studies have shown that blood pressure is positively correlated with carotid IMT in essential hypertension (10)(11). Carotid IMT and plaque formation are also highly associated with hyperlipidemia. Lipid reduction has been demonstrated to delay the progression of atherogenesis and reduce the incidence of cardiovascular morbidity and mortality (12) as well as the incidence of stroke (13)(14). Therefore, control of risk factors such as hypertension and hyperlipidemia can hypothetically stabilize carotid artery IMT and plaque and reduce the morbidity and mortality of cerebrovascular disease. However, the therapeutic benefits of lipid reduction on carotid atherosclerosis and the incidence of stroke in patients with essential hypertension have not been studied. In this study, we compared the combination of the lipid-lowering agent micronized fenofibrate and antihypertensive drugs with antihypertensive therapy alone for inhibiting carotid atherosclerosis in patients with essential hypertension and mild hyperlipidemia.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study population
The present study initially included a total of 594 consecutively enrolled patients diagnosed with essential hypertension (blood pressure >140/90 mm Hg) from September 2001 to June 2003, according to the criteria set by the WHO/International Society of Hypertension (5). The research protocol was approved by the ethics committee of the Clinical Medical College of Shandong University. All participants provided informed consent. The major inclusion criteria were total cholesterol (TC) ≥5.20 mmol/L, LDL-cholesterol (LDL-C) ≥3.40 mmol/L, or triglyceride (TG) ≥2.30 mmol/L, carotid IMT ≥1.0 mm, or atherosclerotic plaque ≥grade 1. Patients with diabetes mellitus, coronary artery disease, previous stroke, renal dysfunction, peripheral vascular disease, chronic inflammatory diseases, or malignant disease were excluded from the study. The incidence of stroke occurring during the 2-year trial period was included in the study data. Of the 225 participants meeting the inclusion criteria, 115 were randomly assigned to the treatment group and 110 to the control group. The sample size of 225 participants enabled detection of a standardized difference of 0.9 at a 2-sided significance value of 0.05 and a power of 0.8.

study design
This was a single-center, open-label trial. Participants randomly assigned to the treatment group by research investigators underwent a 2-week washout period during which they received 160 mg of micronized fenofibrate daily in combination with hypotensive agents (Benazepril 10–20 mg/day and/or Amlodipine 5–10 mg/day) in an attempt to bring the blood pressure to ≤140/90 mm Hg or achieve a 15% reduction of baseline blood pressure. During the 2-week washout period, participants unable to tolerate the medication or those with poor compliance or blood pressure control were excluded from the study. Final-inclusion participants continued to take these medications for 24 months and were maintained on a low-fat diet throughout the study period. In the fenofibrate treatment group, only 9% of participants had side effects after taking the medication. Side effects included dyspepsia, decrease of appetite, flatulence, and epigastric discomfort. Participants from the control group received only antihypertensive drug therapy (Benazepril 10–20 mg/day and/ or Amlodipine 5–10 mg/day) but also remained on a low-fat diet for the same period of time. The primary goal was the evaluation of carotid atherosclerosis, with the secondary goal of evaluating the incidence of stroke after fenofibrate therapy. On the basis of patient symptoms, physical examination, and computed tomographic scan findings, the types of strokes that occurred during the study were identified as hemorrhagic and ischemic, minor ischemic, and transient ischemic attack.

biochemical assays
Blood was collected from patients on 2 separate occasions, after the patients had fasted overnight, at baseline and at the end of the observation period. Serum samples were separated and stored for <3 days in the dark at 4 °C after preparation or –80 °C if not analyzed immediately. Serum TC, HDL cholesterol (HDL-C), and TG were measured on a Beckman Synchrotron LX20 (total CV ≤5%). LDL-C concentrations were calculated based on the Friedewald equation (15). High-sensitivity C-reactive protein (hsCRP) was measured with a near infrared particle immunoassay on the Synchrotron LX20 (total CV ≤7.5%). Serum apolipoprotein B-100 (apoB100) and apoAI were measured by nephelometry with the Beckman ArrayTM Protein System (total CV ≤6%). Cytokines interleukin 1 (IL-1), IL-6, tumor necrosis factor {alpha} (TNF-{alpha}), and interferon {gamma} (IFN-{gamma}) were assayed by ELISA with commercial ELISA reagent sets (R&D Systems; total CV ≤10%). Oxidized LDL (OxLDL) was measured with an ELISA method (Shanghai Rongsheng Biotech; total CV ≤10%) and P-selectin and nitric oxide (NO) concentrations with an ELISA reagent set (Bender MedSystems; total CV ≤10%) and colorimetric assay (R&D Systems), respectively.

ultrasonograph measurements
Ultrasonographic detection of the carotid artery IMT is an effective and noninvasive method for assessment of carotid atherosclerosis. Carotid IMT measured by B-mode ultrasonography is usually performed in the common and internal carotid arteries (9). The IMT, diameter (D), IMT/D ratio, shape and degree of plaque, and extent of stenosis of the common carotid and internal carotid arteries were all determined by ATL-HDI 5000 color-Doppler ultrasonography with an 8.0 MHz linear-array transducer (CV ≤8%) according to the method and procedure previously described (9). To minimize the variation of sonography imaging, 2 sonographers, under blinded conditions, performed measurements, and the values of IMT and D were taken as the means of 10 measurements.

statistical analysis
All data are expressed as mean (SD). Statistical analyses were performed with SPSS14.0 software (SPSS Inc.). The differences between the means of the 2 groups and between the values taken at baseline and the end of intervention period were compared with the t-test. Categorical variable comparison was performed by means of the {chi}2 test. Statistical significance was defined as P <0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
patient demographics
A total of 225 patients (n = 110 for control group, n = 115 for treatment group), with essential hypertension were selected and randomly allocated to this study. Baseline demographic characteristics are listed in Table 1 . Age [61.1 (10.8) vs 60.3 (11.9) years, P >0.05] and sex distribution (68/42 vs 71/44 men/women) were similar between the 2 groups. There was no difference in history for hypertension [12.2 (7.5) vs 12.0 (7.9) years, P >0.05]. Blood pressure was similar between the 2 groups [162 ( (14))/102 (9) vs 163 (15)/102 (9) mm Hg, P >0.05], and serum TC, HDL-C, LDL-C, and TG were also comparable (P >0.05). There were no major differences in the initial carotid IMT between the control and treatment groups [0.94 (0.19) vs 0.95 (0.20) mm, P >0.05] (Table 1 ).


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  		Table 1. Demographic characteristics of patients with essential hypertension for control and treatment groups.

lipid-lowering and antioxidant effects of micronized fenofibrate
Treatment with micronized fenofibrate in combination with antihypertensive agents for 24 months had a significant lipid-lowering and antioxidant effect compared with antihypertensive therapy alone (Table 2 ). Patients receiving micronized fenofibrate in addition to antihypertensive treatment had significant reductions in TC [6.35 (2.08) vs 5.49 (1.88) mmol/L], LDL-C [3.33 (1.03) vs 2.99 (0.99) mmol/L], TG [2.39 (1.15) vs 1.73 (0.97) mmol/L], and apoB100 [1.22 (0.38) vs 1.01 (0.27) g/L] after 24 months of therapy (Table 2 ). In addition, HDL-C [1.32 (0.29) vs 1.58 (0.33) mmol/L, P <0.05] and apoAI [1.19 (0.22) vs 1.31(0.32) g/L] substantially increased after micronized fenofibrate intervention. In the control group, which included patients with essential hypertension who received only antihypertensive therapy, there were no significant changes in serum TC, HDL-C, LDL-C, TG, apoAI, or apoB100. Serum OxLDL concentrations were substantially decreased in the micronized fenofibrate treatment group [1.25 (0.36) vs 1.01 (0.27) mg/L], but there was no significant change compared with baseline values in the control group [1.20 (0.35) vs 1.25 (0.37) mg/L]. Treatment with micronized fenofibrate substantially increased serum NO concentrations [86.50 (22.48) vs 101.32 (27.42) µmol/L], but antihypertensive treatment alone produced no significant change.


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  		Table 2. Lipid-lowering effects of micronized fenofibrate in patients with primary hypertension.

antiinflammatory effects of micronized fenofibrate
Antiinflammatory effects were evaluated in patients with essential hypertension after fenofibrate therapy. Significantly lower concentrations of IL-1 compared with baseline values [6.77 (1.15) vs 8.25 (1.34) ng/L], IL-6 [6.92 (1.69) vs 9.45 (1.48) ng/L], TNF-{alpha} [3.45 (1.03) vs 4.87 (1.24) ng/L], and IFN-{gamma} [5.72 (1.35) vs 9.67 (1.70) ng/L] were achieved in patients treated with micronized fenofibrate and antihypertensives (Table 3 ). Both hsCRP [5.47 (1.09) vs 6.73 (1.38) mg/L] and P-selectin [1.42 (0.40) vs 1.69 (0.45) mg/L] were also decreased after micronized fenofibrate treatment. In contrast, there was an upward trend for IL-1, IL-6, TNF-{alpha}, IFN-{gamma}, hsCRP, and P-selectin, with increased IL-6 concentrations compared with baseline values reaching statistical significance [11.79 (2.15) vs 9.26 (1.59)] in the control group.


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  		Table 3. Antiinflammatory effects of micronized fenofibrate in patients with essential hypertension.

inhibition on progression of carotid artery atherosclerosis
Carotid artery ultrasonography demonstrated that the IMT of hypertensive patients was stable, with some improvements achieved after 24 months of intervention therapy with micronized fenofibrate (Table 4 ). Common carotid artery IMT (CCAIMT) [0.95 (0.20) vs 0.96 (0.21) mm] and internal carotid artery IMT (ICAIMT) [0.87 (0.28) vs 0.87 (0.29) mm] were not significantly different before or after fenofibrate treatment. More importantly, the CCAIMT/D ratio [12.98 (2.62) vs 12.12 (2.26)%] and ICAIMT/D ratio [14.91 (3.66) vs 14.01 (3.18)%, P <0.05] were significantly decreased in the fenofibrate intervention group, but there was an increase in the CCAIMT ratio [0.94 (0.19) vs 0.99 (0.22) mm] and the ICAIMT/D ratio [14.88 (3.88) vs 15.96 (3.92)%] in the control group treated with antihypertensive therapy alone. The incidence of carotid artery plaque formation remained stable in the fenofibrate intervention group (39.22% vs 40.19%) but was substantially increased (39.05% vs 46.67%) in the control group at the end of the 24-month period of observation (Table 4 ). The incidence of stroke in the fenofibrate intervention group was also significantly lower (11.30%) than that observed in the controls (21.82%) (P <0.05) (Fig. 1 ). Each type of stroke and the change in stroke incidence after fenofibrate therapy is listed in Table 5 .


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  		Table 4. Effects of micronized fenofibrate on CCAIMT and IMT/D ratio in patients with essential hypertension.


Figure 1
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  		Figure 1. Incidence of stroke in patients with essential hypertension with and without micronized fenofibrate treatment.

The incidence of stroke in the fenofibrate intervention group was significantly lower (11.30%) than that of the controls (21.82%). * P <0.05.


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  		Table 5. Stroke category in patients with essential hypertension with and without micronized fenofibrate treatment.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The treatment of dyslipidemia alone has shown a beneficial effect on atherosclerosis and hypertension (16). This effect is attributed not only to lipid reduction, but also to the pleiotropic effects of treatment, including enhancement of NO bioavailability, antiinflammatory activity, and inhibition of oxidative stress (17). Several studies have demonstrated the effect of lipid reduction on retardation of carotid IMT progression, but none were conducted in hypertensive patients (18)(19)(20)(21). In our study, we demonstrate that administration of micronized fenofibrate in combination with antihypertensive therapy in essential hypertensive patients can slow the progression of carotid atherosclerosis and decrease the incidence of strokes compared with a control group administered only antihypertensive drugs. In the present study, we did not measure participant body weight, body mass index, waist circumference, or waist/hip ratio, because we judged these variables to be less relevant to stroke in essential hypertension, but they should be considered if significant differences exist between the treatment and control groups. Because we found no differences in age, sex, lipid profiles, or inflammatory markers at baseline values between the control and treatment groups in this study, we did not further analyze and adjust the influence of these variables on the outcomes.

Micronized fenofibrate is a fibric acid derivative that reduces serum TC, LDL-C, TG, and VLDL-cholesterol and increases the concentrations of HDL-C, apoAI, and apoAII (22). A new tablet formulation of micronized fenofibrate (160-mg tablet) has greater bioavailability than the older capsule formulation (200 mg capsule) and demonstrates superior abilities to correct dyslipidemia (23). Previous studies have suggested that the beneficial effects of fenofibrate on lipid profiles may be attributable to enhanced oxidation of fatty acids, increased lipolysis, and plasma clearance of TG-rich VLDL particles, as well as augmentation of apoAI- and apoAII-mediated increases of HDL-C concentrations (24). Recently, researchers have found that fenofibrate can activate the peroxisome proliferator-activated receptors (PPARs), especially PPAR-{alpha}, which in turn controls several genes involved in lipid metabolism, including those encoding for apolipoprotein CIII, apoAI, and apoAII (25), leading to decreased serum concentrations of apoCIII, which in turn lead to increased lipoprotein lipase activity and lipolysis. Activation of PPAR-{alpha} enhances catabolism of VLDL and HDL-mediated reverse cholesterol transport and increases the synthesis of apoAI and apoAII to further enhance the production of HDL (26). We have observed a significant decrease in concentrations of TC, LDL-C, TG, and apoB100, and increase of HDL-C and apoAI after treatment with the new formulation of micronized fenofibrate. In addition, we also demonstrate that administration of micronized fenofibrate decreases OxLDL concentrations in the circulation, which may contribute partially to its atheroprotective effects. The endothelium is a favored early target of hypercholesterolemia and hypertension. Endothelial dysfunction, characterized by decreased bioavailability of NO, promotes the initiation and development of atherosclerotic lesions (27) and hypertension (28). Our data show that fenofibrate enhances NO, suggesting that fenofibrate treatment may improve endothelial function by increasing bioavailability of NO.

Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis (29)(30) and hypertension (31)(32). Recent studies indicate that micronized fenofibrate decreases the serum concentrations of cytokines and hsCRP (33). P-selectin is highly increased in hypertension (34)(35), and its serum concentration is positively correlated with carotid IMT (36). Our study reveals that fenofibrate reduces serum cytokines, hsCRP, and P-selectin. The antiinflammatory property of fenofibrate may play a considerable role against carotid atherosclerosis in essential hypertensive patients.

We set exclusion criteria that were deliberately strict to illustrate the differences more definitively, which may limit the generalizability of the conclusions. Our initial objective was to determine the lipid-lowering effect on carotid atherosclerosis in patients with essential hypertension and eliminate other potential interferences. Inclusion of patients with other disorders might also affect our conclusions. Other limitations of this study also need to be addressed. First, our patients were primarily affected by essential hypertension (with the exclusion of other major relevant disorders), which itself is the major contributing factor for stroke. Second, our study population was limited to Chinese patients. Third, the relatively small sample size from a single center may have affected the calculation of the incidence of stroke. Finally, the strokes we counted in this study included hemorrhagic stroke, ischemic stroke, transient ischemic attack, and minor ischemic stroke. Indeed, transient ischemic attack accounted for one third of the strokes in our study. Because of the small number of strokes (Table 5Up ), we were unable to detect the degree of significance in each category. Therefore, we pooled all of the categories of strokes from each group, and analyzed the difference in the incidence of stroke between the 2 groups. All these factors may limit the applicability of the conclusions to the study of strokes. Therefore, caution needs to be used for data interpretation in this context.

In conclusion, hypertension and hyperlipidemia are 2 major risk factors that affect carotid artery IMT and plaque formation. Carotid IMT and plaque formation are associated with cerebrovascular events. Our study demonstrated that in patients with essential hypertension with mild dyslipidemia, the combination of antihypertensive agents with the lipid-lowering drug micronized fenofibrate attenuates the progression of carotid atherosclerosis and decreases the incidence of stroke. In patients with high risk of both essential hypertension and dyslipidemia, the combined, multitargeted management approach to treat both is a plausible method for cardiovascular disease risk reduction.


   Acknowledgments
 
This study was supported in part by Jinan Science and Technology Research Foundation, Jinan, China.


   Footnotes
 
1 Nonstandard abbreviations: IMT, intima-media thickness; TC, total cholesterol; LDL-C, LDL-cholesterol; TG, triglyceride; HDL-C, HDL-cholesterol; hsCRP, high-sensitivity C-reactive protein; apoB100, apolipoprotein B100; apoAI, apolipoprotein AI; IL-1, interleukin-1; IL-6, interleukin-6; IFN-{gamma}, interferon {gamma}; TNF-{alpha}, tumor necrosis factor; OxLDL, oxidized LDL; NO, nitric oxide; apoAII, apolipoprotein II; D, diameter; CCAIMT, common carotid artery IMT; ICAIMT, internal carotid artery IMT.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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