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Annals of Clinical & Laboratory Science 37:158-166 (2007)
© 2007 Association of Clinical Scientists

Decrease in Inflammatory Cardiovascular Risk Markers in Hyperlipidemic Diabetic Patients Treated with Fenofibrate

Ta-Jen Wu1, Horng-Yih Ou1, Chien-Wen Chou3, Shu-Hwa Hsiao2, Chia-Yin Lin2 and Pai C. Kao4
1 Department of Internal Medicine and 2 Department of Pharmacy, National Cheng Kung University Hospital, Tainan, Taiwan; 3 Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan; 4 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

Address correspondence to Pai C. Kao, Ph.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; e-mail kao.pai{at}mayo.edu.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The goal was to investigate the effect of micronized fenofibrate, a hypolipidemic drug, on inflammatory markers and proinsulin in patients with type 2 diabetes who had hyperlipidemia. Thirty-nine patients were treated with micronized fenofibrate (200 mg/day for 12 wk). Erythrocyte sedimentation rate (ESR), fibrinogen, high-sensitivity C-reactive protein (hs CRP), and proinsulin levels were measured at baseline and after 12 wk of therapy. Micronized fenofibrate significantly reduced serum triglyceride, cholesterol, and uric acid levels (all p <0.0001) and increased high-density lipoprotein (HDL)-cholesterol (p <0.001) and creatinine levels (p <0.0001). Micronized fenofibrate also significantly decreased fibrinogen (421 ± 152 vs 344 ± 81 mg/dl, p <0.001), hs-CRP (3.3 ± 3.3 vs 2.1 ± 1.8 mg/L, p <0.01), and ESR (19.1 ± 24.8 vs 9.7 ± 8.7 mm/hr, p <0.01), but did not change proinsulin levels. The correlations among changes of hs-CRP, fibrinogen, and ESR were high. Although correlation among the decreases in inflammatory markers (ESR, fibrinogen, and hs-CRP) was significant, there was no significant correlation between the changes of lipid profile and inflammatory markers. In conclusion, after 12 wk, micronized fenofibrate therapy significantly decreased 3 inflammatory markers (hs-CRP, ESR, and fibrinogen) and improved the lipid profile by decreasing serum triglyceride, cholesterol, and non–HDL-cholesterol levels and increasing HDL-cholesterol; however, it did not change serum proinsulin level, a pancreatic stress marker.

Keywords: erythrocyte sedimentation rate, fenofibrate, hs-CRP, fibrinogen, proinsulin, diabetes mellitus

Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FIELD, fenofibrate intervention and event lowering in diabetes; FPG, fasting plas ma glucose; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; PPAR{alpha}, peroxisome proliferator–activated receptor-{alpha}.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Fenofibrate is a second-generation fibric acid drug derived from the prototype clofibrate. Compared to first-generation drugs, it has improved efficacy and safety. Fenofibrate has been recommended by the American Diabetes Association for treatment of dyslipidemia in patients with diabetes mellitus [1]. It also has a remarkable effect on increasing serum high-density lipoprotein (HDL)-cholesterol levels and decreasing serum uric acid levels [2–4]. Using high-resolution magnetic resonance imaging, Corti et al [5] found that fenofibrate caused regression of atherosclerotic plaques in hypercholesterolemic rabbits. The Diabetes Atherosclerosis Intervention Study noted improved angiographic findings in diabetic patients with mild dyslipidemia after fenofibrate therapy for 3 yr [6].

The pharmacological mechanisms of feno-fibrate’s effects have not been elucidated completely. Recent studies have shown that fibrates are ligands of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}). Fenofibrate-activated PPAR{alpha} receptor forms a heterodimer with an activated retinoic acid receptor; the heterodimer then binds to the response element on the target gene to produce mRNAs for the synthesis of lipid metabolic enzymes. Thus, it appears that fibrates decrease triglyceride plasma levels through increases in the expression of genes involved in fatty acid-ß oxidation and increasing lipoprotein lipase gene expression. Mitochondria are believed to be the principal target [7]. Another report has indicated that fenofibrate induces gene expression of the mRNA for mitochondrial uncoupling protein 3 and uncoupling protein 2 to increase the metabolic pathways and reduce triglyceride levels [8].

In recent years, several nontraditional risk markers for atherosclerosis, such as high-sensitivity C-reactive protein (hs-CRP), fibrinogen, erythrocyte sedimentation rate (ESR), and plasminogen activator inhibitor-1, have been investigated. Of these, hs-CRP has been studied most widely and has been linked to excessive risk of cardiovascular disease [9]. Inflammation measured by ESR is a significant predictor of heart failure and coronary heart disease, independent of established risk factors [10,11]. C-reactive protein (CRP) appears to be a valuable tool for predicting future vascular events in patients [9]. Because of its long half-life of 19 hr, CRP is a stable marker for monitoring cardiovascular therapy, detecting subclinical diseases, and assessing the wellness of the general population. Healthy diet, good lifestyle, and low body mass index are associated with low serum CRP levels. Lifestyle has a stronger effect on CRP levels than genetics, even in monozygotic twins [12].

The prevalence of hyperfibrinogenemia among patients with type 2 diabetes mellitus is high. Fibrinogen, an inflammatory marker, is independently associated with hemoglobin A1c level and albumin excretion rate, suggesting that fibrinogen may increase the cardiovascular risk of patients with type 2 diabetes mellitus [13].

Our previous study investigated serum proinsulin levels in patients with type 2 diabetes mellitus who required insulin therapy and those who did not require insulin therapy [14]. In both groups, the level of proinsulin was considerably higher than the reference limit (20 pmol/L). The high level of proinsulin persisted for up to 2 yr in patients who required insulin therapy and then gradually decreased; within 12 yr after insulin therapy was initiated, the proinsulin level had decreased to within the reference range [14]. A high concentration of proinsulin has been shown to precede acute myocardial infarction in a nondiabetic population [15]. Thus, proinsulin is considered a marker of insulin resistance and a predictor for high risk for cardiovascular disease [16,17]. Because fenofibrate acts as an agonist of PPAR{alpha}, it may improve insulin sensitivity and reduce adiposity [18,19]. Clinical studies have not reported on the effect of fenofibrate therapy on proinsulin levels.

The present study investigated the effect of micronized fenofibrate on markers for atherosclerosis, including hs-CRP, fibrinogen, ESR, and proinsulin, and the relations among these multiple effects in patients with type 2 diabetes mellitus and metabolic syndrome after 12 wk of treatment with fenofibrate.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Subjects.  Thirty-nine patients were recruited from the outpatient clinic of the Endocrine Division at the National Cheng Kung University Hospital, Taiwan. On the basis of clinical characteristics, including the absence of ketoacidosis, age >20 yr at the time of diagnosis of diabetes, treatment with oral hypoglycemic agents, or a fasting C-peptide level >0.30 nmol/L, type 2 diabetes mellitus was diagnosed in all patients. They had hyperlipidemia, as defined by fasting serum cholesterol level =200 mg/dl or fasting serum triglyceride level =200 mg/dl (or both) that was not normalized by at least 3 mo of diet therapy. The patients were clinically stable, with glycemic control, and had not taken any lipid-lowering drugs for at least 2 mo. In addition to type 2 diabetes mellitus and hyperlipidemia, the patients had at least one other component of the metabolic syndrome (eg, hypertension or obesity). Hypertension was defined as systemic blood pressure of 130/85 mm Hg or higher. Obesity was defined as a body mass index of =27 or a waist circumference of =90 cm in men and =80 cm in women. These are standards modified by Adult Treatment Panel III of the Department of Health in Taiwan to fit the local population.

Patients were excluded from the study if they were taking another medication (such as oral contraceptives, probucol, statins, oral anticoagulants, thiazides, ß-blockers, metformin) capable of interfering with lipid metabolism or if they had a medical history of hypothyroidism, pancreatitis, cholestasis, nephrotic syndrome, chronic alcoholism, myocardial infarction, cerebrovascular stroke, cardiovascular surgery, unstable or recent angina pectoris, gastric or peptic ulcer, or an identified acute or chronic infectious disease. Patients who had unstable diabetes mellitus (fasting plasma glucose [FPG] >300 mg/dl on 2 successive visits), poorly controlled hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg), elevated liver enzymes (=2.5 times the upper normal limits), or increased serum creatinine (>1.9 mg/dl) were also excluded.

Study design and assessment.  Patients deemed eligible at screening were asked to continue the therapeutic lipid-lowering diet recommended by the guidelines of the National Cholesterol Education Program [20] and continue taking hypoglycemic agents to maintain FPG <250 mg/dl and HbA1c <11% without ketosis. During the 4 wk period of dietary therapy, the recommended diet and hypoglycemic agents were held constant. After the dietary therapy was completed, one 200 mg capsule of micronized fenofibrate, taken daily with the first mouthful of food in the morning, was added to the regimen. When patients entered the study, they were instructed to follow the recommended diet throughout the entire period. All current medications were kept constant throughout the study. Before the study was initiated, its protocol was approved by the Clinical Trial Committee of the National Cheng Kung University Hospital. All eligible patients gave written informed consent before participating in the trial.

Blood collection and assays.  Blood samples were collected in the morning after an overnight 12-hr fast from all patients. Blood was drawn from the antecubital vein, with the patient seated. Blood ESR and HbA1c, serum total cholesterol, HDL-cholesterol, triglycerides, glucose, creatinine, uric acid, hs-CRP, proinsulin, and plasma fibrinogen were assayed before and after 12 wk of micronized fenofibrate treatment.

Serum total cholesterol, triglycerides, HDL-cholesterol, uric acid, and creatinine levels were determined in the central laboratory of National Cheng Kung University Hospital with an autoanalyzer (Hitachi 747E, Tokyo, Japan). Because the patients also had metabolic syndrome, non-HDL-cholesterol was calculated by subtracting total cholesterol from HDL-cholesterol [20]. Serum glucose was measured by the hexokinase method (Roche Diagnostics, Mannheim, FRG) with an autoanalyzer (Hitachi 747E). HbA1c was measured with a high performance liquid chromatographic method (Tosoh Automated Glycohemoglobin Analyzer HLC-723 GHbV A1c 2.2; intra-assay CV of 0.5%, interassay CV of 2.0%).

High-sensitivity C-reactive protein was measured by a highly sensitive latex-based immunoassay (Dade Behring Diagnostics, Inc., Newark, DE) before and after 12 wk of fenofibrate therapy. Polystyrene particles coated with monoclonal antibodies to CRP are agglutinated when mixed with samples containing CRP. The intensity of scattered light in the nephelometer depends on the CRP content of the sample; therefore, the CRP concentration can be determined against dilutions of a standard of a known concentration. According to the manufacturer’s insert, the upper normal limits of CRP in serum of 2,147 apparently healthy subjects were 1.69 mg/L (90th percentile) and 2.87 mg/L (95th percentile).

Plasma fibrinogen level was determined with the PT-fibrinogen kit (HemosIL, Instrumentation Laboratory, Milan, Italy). With the IL coagulation system, fibrinogen is quantified (PT-based method) by relating to a calibrator the absorbance or light scatter during clotting. The assay has an intra-assay CV of 3.54% and interassay CV of 6.45%.

Erythrocyte sedimentation rate (ESR) was determined with a Sediplast kit (Lpitaliana SPA, Milan, Italy) according to the Westergren method.

Proinsulin was measured with a DRG Proinsulin ELISA kit (DRG International Inc., East Mountainside, NJ), which has a sensitivity of 0.5 pmol/L. The assay has an intra-assay CV of 2.9–7.4% and an interassay CV of 5.5–6.8%.

Statistics.  All data were expressed as mean ± SD. The software package of JMPIN (SAS Institute, Cary, NC) was used to analyze the data. Shapiro-Wilk W test for normality was used to test the normal distribution. The paired t test was used to compare the changes of parameters before and after fenofibrate therapy. The Spearman nonparametric measure of association was used to analyze the correlation among the changes of hs-CRP, fibrinogen, and ESR and metabolic parameters such as serum uric acid, triglyceride, total cholesterol, and HDL-cholesterol level at the end of the 12 wk of treatment. Statistical significance was fixed at p <0.05, as indicated (2-tailed test).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
After 12 wk of therapy, micronized fenofibrate significantly improved the lipid profile by decreasing the serum levels of triglyceride, total cholesterol, non-HDL-cholesterol and increasing the level of HDL-cholesterol. Micronized fenofibrate also decreased the serum concentrations of uric acid and slightly increased the serum creatinine level. It also significantly decreased the inflammatory markers fibrinogen, hs-CRP, and ESR, but it did not change the serum proinsulin level (Table 1Go). One patient had a CRP of 16.1 mg/L, ESR of 130 mm/hr, and fibrinogen of 1,111 mg/dl before treatment with micronized fenofibrate but no noticeable inflammation.


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  		Table 1. Clinical and metabolic characteristics before and after 12 wk of micronized fenofibrate therapy in 39 patients with type 2 diabetes mellitus and hyperlipidemia (values are means ± SD).
 
The correlation matrix among the changes of hs-CRP, fibrinogen, and ESR and metabolic parameters such as serum levels of uric acid, triglyceride, total cholesterol, and HDL-cholesterol at the end of the 12-week treatment, according to Spearman nonparametric measures, is shown in Table 2Go. The correlation among the changes of hs-CRP, fibrinogen, and ESR was significantly high. There also was a significant correlation between the changes of triglyceride and HDL-cholesterol.


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  		Table 2. Changes of serum lipid profile (triglyceride, total cholesterol, and HDL-cholesterol) and cardiovascular risk factors after 12 wk of fenofibrate treatment in 39 patients with type 2 diabetes mellitus and hyperlipidemia.*
 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The incidence of coronary heart disease in diabetic patients is associated with many known classic risk factors such as hypertension, smoking, increased total serum cholesterol, and decreased HDL-cholesterol. A study has reported an association between the incidence of coronary heart disease and waist-hip ratio, levels of HDL-cholesterol, apolipoproteins (apo) A-1 and B, serum albumin and plasma fibrinogen levels [21]. In addition to a marked improvement in the lipid profile and uric acid levels, our study demonstrated that micronized fenofibrate significantly decreased nontraditional cardiovascular risk markers such as hs-CRP and fibrinogen levels and ESR in patients with type 2 diabetes mellitus and hyperlipidemia.

As reported by Choi et al [22], hs-CRP concentrations are higher in elderly Korean women with impaired glucose tolerance than in those with normal glucose tolerance. According to a study of patients with advanced atherosclerosis, hs-CRP, and HbA1c jointly predict future cardiovascular risk [23]. Recent studies have reported that fenofibrate decreases the levels of hs-CRP in dyslipidemic hypertensive patients [24] and dyslipidemic obese patients [25].

Compared to previous studies that reported a decrease in serum hs-CRP of 29.8% to 51.7% in patients with hyperlipidemia [26–28], 34% in hypertriglyceridemic men [29], 67% in dyslipidemic hypertensive patients [24], and 74.1% in patients with dyslipidemic obesity [26], our study demonstrated a 36% decrease in patients with metabolic syndrome after 12 wk of fenofibrate therapy. The mechanism by which long-term fenofibrate treatment decreases serum hs-CRP is thought to be associated with the suppression of interleukin-6–induced acute phase response gene expression [30,31]. The role of hs-CRP in the pathogenesis of atherosclerosis is receiving increased attention because of the effect of hs-CRP on the production of the chemokine monocyte chemo-attractant protein-1, which is abolished by fenofibrate but not by aspirin [32]. CRP promotes monocyte chemoattractant protein 1–mediated chemotaxis through upregulating CC chemokine receptor 2 expression in human monocytes [33]. Thus, by reducing CRP levels, fenofibrate may reduce monocyte chemotaxis and, thereby, atherogenesis by decreasing the expression of both the chemokine and its receptor. Each CRP molecule consists of 5 identical protomers; each protomer has 2 calcium ions that bind to LDL to form a complex. This complex induces the formation of foam cells on the endothelial cell wall, attracting monocytes. Thus, a high level of CRP is both a marker and a cause of atherosclerotic lesions. Twelve wk of fenofibrate therapy decreased CRP levels, which would be predicted to reduce the risk of atherosclerosis.

Fibrinogen has also been reported to be an independent risk factor for coronary heart disease [13]. Patients with angina pectoris who have low levels of fibrinogen also have a low risk of myocardial infarction and sudden death [34]. Similar to CRP, fibrinogen is an acute phase protein in response to inflammation, but its response is slower and the incremental percentage is less than that of CRP [35]. Fenofibrate decreases the levels of fibrinogen and CRP in patients who have coronary artery disease [36]. Fenofibrate may have beneficial effects on CRP and fibrinogen in patients with impaired glucose tolerance. In a short-term study of only 30 days of fenofibrate treatment, the impaired glucose tolerance test improved by 14% because of increased insulin sensitivity. Increased insulin sensitivity may decrease insulin requirement that decreases the proinsulin level [37]. In our study, we expected to detect a decrease in proinsulin level. However, the minute change of proinsulin from 45 ± 16 to 44 ± 15 pmol/L after 12 wk of treatment was statistically insignifcant (Table 1Go).

Our study detected 18% decrease in the plasma fibrinogen level in patients with type 2 diabetes mellitus and metabolic syndrome (p <0.001), which is consistent with results of previous studies that showed a 16% to 17% decrease in patients without diabetes [38,39]. A recent study by Saklamaz et al [40] indicated that fenofibrate, but not pravastatin or atorvastatin, has significant beneficial effects on fibrinogen levels of patients with hyperlipidemia. ESR has also been reported to be an independent risk factor for the development of heart failure [10] and coronary heart disease [11]. Currently, no study has reported on the effect of fenofibrate on ESR; however, in our patients with type 2 diabetes mellitus and metabolic syndrome, fenofibrate decreased ESR 47.7% (p <0.01) (Table 1Go).

The decreases in hs-CRP, fibrinogen, and ESR were highly correlated with one another, as our results indicated (Table 2Go). The decrease in hs-CRP and fibrinogen was independent of a lipid-lowering effect, but the decrease in ESR correlated slightly with a decrease in cholesterol. Among these inflammatory markers, the changes in hs-CRP level are consistent with the results of studies in transgenic mice and cultured hepatocytes [30] and with a clinical study [41]. Whether or not the effects of decreasing fibrinogen, CRP, and ESR act synergistically to affect morbidity and mortality requires further long-term studies.

Fenofibrate may alleviate fatty acid-mediated inhibition of insulin-mediated glucose disposal [19]. Clinically, a study of well-controlled type 2 diabetic patients showed that gemfibrozil treatment improves both glucose and lipid profiles because of a significant amelioration in insulin action [42]. However, other reports have not shown improvement in insulin action [28,43,44]. Recently, increased proinsulin levels have been considered to be a stronger predictor of cardiovascular disease mortality than insulin [15,16]. Proinsulin is also considered to be closely associated with insulin resistance [17,37,45]. Moreover, Haffner et al [46] have suggested that proinsulin is a marker of atherosclerosis. These authors did not investigate an effect of fenofibrate treatment on plasma glucose or proinsulin levels in patients who had type 2 diabetes mellitus and hyperlipidemia, as discussed above. Our current observations suggest that micronized fenofibrate has no effect on ß cell secretion in diabetic patients.

The Adult Treatment Panel III of the National Cholesterol Education Program stated that diabetes should be considered a coronary heart disease risk equivalent [16]. Therapy for this condition should be intensive and multifactorial. Because patients with type 2 diabetes mellitus frequently have metabolic syndrome, pharmacotherapy beyond antidyslipidemia would be appropriate. Our results demonstrate that micronized fenofibrate has additional anti-inflammatory effects but no effect on proinsulin (Table 1Go).

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study [47], a comprehensive randomized controlled trial of long-term fenofibrate therapy in 9,795 patients with type 2 diabetes mellitus (4,895 received 200 mg micronized fenofibrate daily—the same dose we used—and 4,900 received placebo), reported that fenofibrate decreased total cardiovascular events of cardiovascular death, myocardial infarction, stroke, and coronary and carotid revascularization. However, it did not decrease the risk of coronary heart disease death and nonfatal myocardial infarction. It also slightly increased the risk of pancreatitis (p = 0.031). Although adverse drug reactions, such as pancreatitis, venous thrombosis, and sudden death, were major concerns [48], we did not find any such side effects in our patients. A study reported that coenzyme Q10 supplementation significantly improved hyperlipidemia, uric acid, and blood pressure during fenofibrate treatment [49]. Whether adding coenzyme Q10 to fenofibrate treatment could improve the drug’s efficacy and decrease adverse drug reactions by decreasing the dose of fenofibrate needs to be elucidated. The FIELD investigators warned that a moderate treatment benefit may have been masked by a higher proportion of patients in the placebo group who had started statin therapy [48].

According to a 2-yr study of bezafibrate, this drug attenuated the process of insulin resistance in type 2 diabetes mellitus [50]. Although increased proinsulin levels are a phenomenon of insulin resistance, the bezafibrate study did not include the measurement of proinsulin levels. One of our primary goals was to detect an effect of fenofibrate on proinsulin levels. However, 12 wk of fenofibrate therapy may not be long enough to detect a change in proinsulin level. A longer-term study, for example, 2 yr of treatment with fenofibrate, might possibly detect an effect on proinsulin level.

The current study is limited by the relatively small number of patients and the relatively short duration. A study of a larger number of patients for a longer period may be needed to elucidate the multiple effects of fenofibrate on cardiovascular risks. It should be emphasized that our study was performed on Taiwanese diabetic patients with hyperlipidemia and may not be applicable to other ethnic groups. It has been demonstrated that Asians may have lower CRP levels than westerns because of differences in diet and lifestyle [12].

In conclusion, micronized fenofibrate improves dyslipidemia and inflammatory markers such as triglyceride, total cholesterol, HDL-cholesterol, non-HDL-cholesterol, fibrinogen, CRP, and ESR, but does not change proinsulin levels in patients with metabolic syndrome associated with type 2 diabetes mellitus and hyperlipidemia.


   Acknowledgments
 
The authors thank diabetes educator Ming-Chao Lee and laboratory technician Su-Gin Hu at the Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, for their expert assistance in patient education, blood sampling, laboratory procedures, and data collection. Editing, proofreading, and reference verification were provided by the Section of Scientific Publications, Mayo Clinic.


   References
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 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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