**2.1.2 Antioxidant actions**

Oxidative stress has been considered to promote aging (Harman, 1978; Yu & Chung, 2001; Romano et al., 2010). As for oxidative stress markers that can be measured on clinical examination, serum lipids, MDA-LDL and Ox-LDL, and urinary lipids, 8-OHdG and 15 isoprostane F2t: 8-epi-PGF2α/8-isoPGF2α, are employed (Harman, 1978; Yu& Chung, 2001). Coenzyme Q10 (CoQ10), also known as ubiquinone shows antioxidant actions and has been monitored as an in vivo marker of oxidative stress.

CoQ10 is biosynthesized from mevalonic acid in the liver. As the pathway of CoQ10 biosynthesis is partially overlapped with that of cholesterol synthesis, the administration of an HMG-CoA reductase inhibitor, statins, reduces the production of CoQ10. Therefore,

Fenofibrate: Panacea for Aging-Related Conditions? 451

mg to healthy adults decreased the serum uric acid level by approximately 1.5 mg/dL. In Japan, fenofibrate has been administered to metabolic syndrome patients with hyperuricemia, leading to the decrease in the serum uric acid level by approximately 2

Large-scale, randomized, controlled clinical trials of fenofibrate involving type II DM, that is, high-risk patients for arteriosclerosis, were conducted. The representative 3 studies were reviewed in this section: "DAIS" study, regarding coronary arteriosclerosis retraction, "FIELD" study, in which the inhibitory effects on cardiovascular events were examined, and "ACCORD" study, in which the inhibitory effects of lipid-intensified therapy with statins on

The DAIS is a placebo-controlled, double-blind, comparative study to verify whether the deterioration of coronary arteriosclerosis can be prevented by restoring abnormal lipid metabolism with fenofibrate in type II diabetics employing quantitative coronary angiography (DAIS investigators, 2001). This international, interventional study was conducted based on the World Health Organization (WHO)'s request and cooperation. This study is the first interventional study in which it was prospectively evaluated whether the correction of disturbance of lipid metabolism in type II DM prevents the deterioration of arteriosclerosis. It was carried out in Canada, Finland, Sweden, and France. Four-hundred and eighteen patients with type II diabetes in whom blood sugar control was favourable were randomly divided into fenofibrate (micronized fenofibrate, 200 mg/day, n=207) and placebo (n=211) groups to evaluate the deterioration of coronary arteriosclerosis using quantitative coronary angiography after 38-month (mean duration)

In the fenofibrate group, a decrease in the minimum lumen diameter and an increase in the percent stenosiswere significantly suppressed in comparison with the placebo group (by 40%), confirming the inhibitory effects of fenofibrate on the deterioration of coronary

In the continuing study of DAIS, fenofibrate reduced the small dense LDL level, leading to the inhibition of the deterioration of diabetic nephropathy (DAIS investigators, 2003, 2005), confirming that fenofibrate inhibited the deterioration of macro- and micro-angiopathy in

The FIELD is a study to verify the inhibitory effects of fenofibrate on cardiovascular events involving approximately 10,000 patients with type II DM (FIELD investigators, 2005). It was conducted in Finland, Australia, and New Zealand. The subjects were 9,795 type II diabetics with mild dyslipidemia. They were randomly divided into fenofibrate (micronized fenofibrate, 200 mg/day, n=4,895) and placebo (n=4,900) groups. Each agent was

In the fenofibrate group, this agent inhibited the incidence of coronary events by 11% in comparison with the placebo group. Unfortunately, there was no significant difference between two groups. This was possibly because statins were combined with the

**2.2.2 Fenofibrate Intervention and Event Lowering in Diabetes Study (FIELD)** 

mg/dL.

administration.

type II DM.

arteriosclerosis in type II DM.

administered for 5 years.

**2.2 Randomized controlled trial (RCT)** 

cardiovascular events were investigated.

**2.2.1 Diabetes Atherosclerosis Intervention Study (DAIS)** 

statins, represented by atorvastatin, also inhibit CoQ10 biosynthesis in vivo, leading to the increase in oxidative stress (Mabuchi et al., 2005).

The administration of standard fenofibrate at 150 mg/day to 18 Japanese type II DM with dyslipidemia for 12 weeks significantly decreased the triglyceride (TG) level (from 232±109 to 145±74 mg/dL, -37%, p<0.01), and significantly improved the HDL-C level (from 45±8.7 to 52±9.8 mg/dL, +14%, p<0.01) (Asano et al., 2006).

The plasma ubiquinol-10 level in fenofibrate group increased significantly after 8 weeks (from 768±265 to 886±310 nM, p<0.05) and after 12 weeks (from 768±265 to 894±336 nM, p<0.05). However, total plasma CoQ10 level (ubiquinol-10 plus ubiquinone-10) as an oxidative stress marker, decreased in statin group, elevated in fenofibrate group after 12 weeks administration (from 1010±296 to 1070±285 nM, +6%). In addition, plasma ubiquinone-10 in fenofibrate group decreased insignificantly. Fenofibrate treatment elevates plasma CoQ10, especially plasma ubiquinol-10 level.

In the wild-type mice administered by diethylhexylphthalate (DEHP: PPAR-α activator), elevation of plasma ubiquinone was significant, but the elevation was not observed in the PPAR-α-null mice (Turunen et al., 2000). In addition, the expression of PPAR-α gene was regulated in the liver of SAMP1 (senescence accelerated mouse prone 1) mice given ubiquinol for long term (Schmelzer et al., 2010a, 2010b). Although the antioxidant action mechanisms of fenofibrate remained unclear in human, mice studies suggested the direct interaction between CoQ10 and PPAR-α.

Fenofibrate not only restores the serum lipid profiles, but also suppresses oxidative stress. Fenofibrate with a variety of pleiotropic activities may protect the pathogenesis and progression of aging-associated atherosclerosis.
