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

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 administered for 5 years.

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

Fenofibrate: Panacea for Aging-Related Conditions? 453

In the ACCORD-Lipid study, the inhibitory effects of 3 intensified/standard medicinal therapies (blood sugar, blood pressure, lipids) on compound cardiovascular events were investigated in approximately 10,000 type II diabetics with mild dyslipidemia and the high risk of cardiovascular disease (CVD) under the auspices of the National Institutes of Health (NIH). Lipid intervention was performed in 5,518 patients: intensified (simvastatin 20mg + micronized fenofibrate 200mg) and standard (simvastatin 20mg + placebo) therapies. The mean follow-up was 4.7 years. In the fenofibrate-combined group, the incidence of cardiovascular events was inhibited by 8%, although there was no significant difference. In patients with a pre-treatment TG level of 204 mg/dL or more and HDL-C level of 34 mg/dL or less, significant inhibitory effects on events were confirmed (-31% (p<0.05), NNT=20)

In the ACCORD–EYE study, the deterioration of diabetic retinopathy was evaluated in 2,856 patients from whom informed consent was obtained (lipid intervention: 1,593 patients) among type II DM who participated in the ACCORD-Lipid study (ACCORD Study Group; ACCORD Eye Study Group et al., 2010). In the fenofibrate-combined group, intensified therapy significantly inhibited the deterioration of diabetic retinopathy (by 40%) in comparison with the simvastatin group (p=0.006). The ACCORD–EYE study, the second large-scale clinical study following the FIELD, demonstrated the inhibitory effects of fenofibrate on the deterioration of diabetic retinopathy, supporting its efficacy for diabetic

The inhibitory effects of fenofibrate on diabetic microangiopathy are summarized below (Table 1). In a large-scale clinical study of lipid-lowering agents, no statin exhibited any inhibitory effects on diabetic microangiopathy. Only fenofibrate inhibited the complication. Thus, fenofibrate should be recognized as a "prophylactic drug for diabetic complications",

Fenofibrate is a generalized, PPAR-α-mediated, serum lipid-lowering agent. In this chapter, the pleiotropic effects of fenofibrate other than serum lipid-lowering actions were primarily reviewed. Concerning to the anti-inflammatory actions, we examined the effects of fenofibrate in patients with a representative inflammatory disorder, RA. Although there were no significant changes in inflammation parameters including CRP and ESR, improvement in the ΔVAS and PSL dose was achieved in patients receiving fenofibrate. In particular, improvement in the ΔVAS was significantly correlated with a reduction in the ΔCRP level, suggesting that the anti-inflammatory effects of fenofibrate may contribute the

In Japan, infectious diseases have been the major causes of death in patients with RA (Souen, 2007; Shinomiya et al., 2008). However, the proportion of cardiovascular events represented by cerebral/myocardial infarction has been increasing, probably because of the changes in life-style (Goto et al., 2008a). So, fenofibrate with lipid-lowering, antiinflammatory and anti-oxidant actions may be appropriate for reducing disturbances of

With respect to antioxidant actions, fenofibrate, but not statin increased the plasma level of ubiquinol-10: a family of CoQ10. As fenofibrate exhibits antioxidant actions, combination

**2.2.3 ACCORD-Lipid & ACCORD-EYE study** 

(ACCORD Study Group et al., 2010).

and not solely as a lipid-lowering agent.

improvement in the patient's quality of life (QOL).

lipid metabolism and also homeostasis in Japanese patients with RA.

retinopathy.

**3. Conclusion** 

placebo/fenofibrate in 32% of patients receiving the placebo and in 16% of patients receiving fenofibrate, reducing the effects of fenofibrate alone. Fenofibrate decreased the incidence of non-fatal myocardial infarction by 24% (p<0.05) and that of total cardiovascular events by 11% (p<0.05), confirming its efficacy.

In primary prevention patients without a history of cardiovascular disease, accounting for approximately 80%, fenofibrate significantly inhibited the incidences of coronary (by 25%) and total cardiovascular (by 19%) events in comparison with the placebo group. Furthermore, in the FIELD, fenofibrate inhibited the onset of diabetic nephropathy, deterioration of diabetic retinopathy, proportion of patients undergoing lower-limb amputation, and deterioration of diabetic neuropathy (FIELD investigators, 2005, 2007, 2009, 2010, 2011). As fenofibrate reduced DM-associated 3 major complications (retinopathy, nephropathy and neuropathy), this agent may be useful for treating diabetic complications.


Table 1. Inhibitory effects of fenofibrate on diabetic angiopathy in a large-scale clinical study involving type II DM

placebo/fenofibrate in 32% of patients receiving the placebo and in 16% of patients receiving fenofibrate, reducing the effects of fenofibrate alone. Fenofibrate decreased the incidence of non-fatal myocardial infarction by 24% (p<0.05) and that of total cardiovascular

In primary prevention patients without a history of cardiovascular disease, accounting for approximately 80%, fenofibrate significantly inhibited the incidences of coronary (by 25%) and total cardiovascular (by 19%) events in comparison with the placebo group. Furthermore, in the FIELD, fenofibrate inhibited the onset of diabetic nephropathy, deterioration of diabetic retinopathy, proportion of patients undergoing lower-limb amputation, and deterioration of diabetic neuropathy (FIELD investigators, 2005, 2007, 2009, 2010, 2011). As fenofibrate reduced DM-associated 3 major complications (retinopathy, nephropathy and neuropathy), this agent may be useful for treating diabetic complications.

Rate of decrease

progression in albumin excretion fenofibrate 8%, Placebo 18%

incidence of microalbuminuria fenofibrate 38.2%, Placebo 41.6%

macroalbuminuria fenofibrate 10.5%, Placebo 12.3%

Table 1. Inhibitory effects of fenofibrate on diabetic angiopathy in a large-scale clinical study

retinopathy -40% p=0.006

in the relative risk p value Reference

nephropathy -14% p=0.002 FIELD investigators,

retinopathy -31% p<0.001 FIELD investigators,

amputation -36% p=0.02 FIELD investigators,

neuropathy -40% p=0.009 FIELD investigators,

2010 incidence of

p=0.01

p=0.04

p<0.05 DAIS investigators, 2005

2005, 2011

2007

2009

2010

ACCORD Study Group,

ACCORD Study Group; ACCORD Eye Study

Group, 2010

events by 11% (p<0.05), confirming its efficacy.

angiopathy

nephropathy

Diabetic

Diabetic

Diabetic

Diabetic nephropathy

Lower-limb

Study name Micro/macro-

DAIS Diabetic

FIELD

ACCORD-Lipid

ACCORD-EYE Diabetic

involving type II DM
