對非糖尿病合併型血脂肪過高患者使用PPARg agonist、PPARa agonist、或HMGCoA還原酶對各種嶄新心血管疾病危險因子之影響
Date Issued
2004
Date
2004
Author(s)
王宗道
DOI
922314B002310
Abstract
Background: Combined hyperlipidemia is characterized by elevated levels of total
cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides and decreased
levels of high-density lipoprotein cholesterol (HDL-C). It is the pathognomonic dyslipidemia
observed in individuals with insulin resistance syndrome. However, it is still uncertain
whether PPARg agonist (e.g. rosiglitazone) had beneficial effects on the prevention of
coronary heart disease (CHD) in individuals with combined hyperlipidemia. Moreover, given
that combination therapy with fibrate plus statin confers a risk of rhabdomyolysis, it is also
worthwhile to determine whether optimal therapy for patients with combined hyperlipidemia
should consist of fibrate monotherapy or statin monotherapy. Until now, however, no
head-to-head comparison of the therapeutic effects (on CHD events) of fibrate monotherapy
with statin monotherapy in individuals with combined hyperlipidemia has been published. In
this study, we will compare the effects of PPARg agonist, statin monotherapy and fibrate
monotherapy on both endothelial function and markers of inflammation (hs-CRP, IL-1, IL-6,
sCD40, and sCD40L), as surrogate indicators of future CHD, in patients with combined
hyperlipidemia. We will further examine the therapeutic effects of these agents in subgroups
stratified by various baseline characteristics and genotypes of eNOS (4a/b and Glu298Asp) to
see if there were any differential effects among these agents.
Methods: Eligible patients, aged 18 to 80 years with plasma triglyceride levels between 200
and 500 mg/dL, total cholesterol level =200 mg/dL, and total cholesterol/HDL cholesterol
ratio>5, will be instructed to adhere to the AHA Step 1 diet throughout the study and undergo
an 8-week run-in period during which previous lipid-lowering therapy will be discontinued.
After the run- in phase, patients will be randomized to receive rosiglitazone (4 mg/d)(n = 40),
simvastatin (20 mg/d)(n = 40) or micronized fenofibrate (200 mg/d)(n = 40) for 8 weeks. The
patients will be seen at the screening visit (i.e. before the 8-week run- in), 1 week before
randomization, at entry (randomization), and 4 and 8 weeks of treatment. Two fasting blood
samples will be obtained at baseline 7 days apart and at the end of the 8-week drug-therapy
phase (weeks 7.5 and 8). Endothelium-dependent flow- mediated vasodilation in response to
reactive hyperemia and nitroglycerin- induced vasodilation will be evaluated in the right
brachial artery 1 week before randomization and after 8 weeks of active treatment.
Results and Clinical Significance: Our study for the first time demonstrated that simvastatin,
fenofibrate, and rosiglitazone markedly reduced plasma levels of high-sensitivity CRP, IL-1,
and sCD40L, and improved endothelium-dependent FMD without mutual differences. The
improvement in FMD with fenofibrate treatment correlated inversely with baseline HDL-C
levels, whereas the improvement in FMD with simvastatin treatment was positively related to
HDL-C levels. Accordingly, in the subgroup with a baseline HDL-C of £ 40 mg/dl, only
fenofibrate significantly improved the endothelium-dependent FMD. On the other hand, in the
subgroup with HDL-C > 40 mg/dl, only treatment with simvastatin achieved significant
improvement in FMD. Furthermore, we demonstrated the safety and benefits of rosiglitazone
use in ameliorating endothelial dysfunction and inflammation, reversing insulin resistance,
and lowering blood pressures in non-diabetic patients with the metabolic syndrome. The
predictive value of eNOS polymorphisms studied on pharmacological responses has not been
proved.
Subjects
endothelium
fibrate
insulin sensitizer
hyperlipidemia
statins
SDGs
Publisher
臺北市：國立臺灣大學醫學院內科
Type
report
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