對非糖尿病代謝症候群患者單獨使用胰島素增敏劑或statins或合併使用兩者對代謝症候群各成份、血管內皮細胞功能、及炎性反應指標之影響：兼論患者基因形態對藥物效應之交互作用
Date Issued
2005
Date
2005
Author(s)
王宗道
DOI
932314B002220
Abstract
Background: The metabolic syndrome consists of insulin resistance, compensatory
hyperinsulinemia, hypertension, hypertriglyceridemia, low HDL-C, and obesity. It has been
demonstrated that the common denominator of the metabolic syndrome is insulin resistance.
Rosiglitazone is a thiazolidinedione (glitazone) developed to reduce insulin resistance in patients
with type 2 diabetes. We and other investigators have recently demonstrated that rosiglitazone
improved insulin sensitivity and endothelial function, and reduced plasma levels of various
inflammatory markers, without causing hypoglycemia, in non-diabetic insulin-resistant subjects.
However, we also found that rosiglitazone therapy resulted in untoward changes in lipoprotein
metabolism, including increases in LDL-C and apolipoprotein B levels. Given that treatment with
rosiglitazone is associated with a worsening of the lipid profile, combination therapy with
rosiglitazone plus statins may be an ideal therapeutic option for non-diabetic patients with the
metabolic syndrome.
In this study, we compared the efficacy of rosiglitazone and statin monotherapy (simvastatin),
and in combination, on endothelial function and CRP as well as other novel inflammatory
markers, as surrogate indicators of future CHD, and components of the metabolic syndrome in
non-diabetic patients with the metabolic syndrome. Furthermore, we analyzed the polymorphism
status of various candidate genes (PPAR γ ) and examined whether there is differential response to
both study medications.
Methods and Materials: Eligible patients, aged 18 to 80 years conformed to the metabolic
syndrome criteria in ATP III, 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 = 25), simvastatin (20 mg/d)(n = 25), rosiglitazone (4 mg/d) plus simvastatin (20
mg/d)(n= 25) or matched placebo (n = 25) for the 8-week double-blind phase. 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: Combination therapy with rosiglitazone and simvastatin did
not result in a greater improvement in endothelial function than either agent alone in the present
study. On the other hand, combination therapy did result in a greater reduction in hs-CRP and
CD40 ligand levels than either agent alone, though not statistically significant. Possible
explanations for our observation include small sample size, chance finding, or ceiling effect of
rosiglitazone on FMD that made further improvement almost impossible. The anti-atherogenic
effect of the two most promising pharmacological agents, statins and glitazones, are additive in
view of their effects on inflammatory markers. The improvement in FMD independently
correlated with changes in endothelin-1 (r=-0.64, p<0.001) and apolipoprotein B (r=-0.34,
p=0.025) levels. Genetic polymorphism studied is not associated with differential response to the
study drugs.
Subjects
endothelium
inflammation
insulin resistance
insulin sensitizer
statins
SDGs
Publisher
臺北市：國立臺灣大學醫學院內科
Type
report
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