All
fibrates are
peroxisome proliferators-activated receptors (PPARs)-alpha agonists with ability to decrease
triglyceride and increase
high density lipoprotein- cholesterol (HDL-C). However,
bezafibrate has a unique characteristic profile of action since it activates all three
PPAR subtypes (alpha, gamma and delta) at comparable doses. Therefore,
bezafibrate operates as a pan-agonist for all three
PPAR isoforms. Selective
PPAR gamma agonists (
thiazolidinediones) are used to treat
type 2 diabetes mellitus (T2DM). They improve
insulin sensitivity by up-regulating adipogenesis, decreasing
free fatty acid levels, and reversing
insulin resistance. However, selective
PPAR gamma agonists also cause water retention,
weight gain, peripheral
edema, and
congestive heart failure. The expression of
PPAR beta/ delta in essentially all cell types and tissues (ubiquitous presence) suggests its potential fundamental role in cellular biology.
PPAR beta/ delta effects correlated with enhancement of
fatty acid oxidation, energy consumption and adaptive thermogenesis. Together, these data implicate
PPAR beta/delta in fuel combustion and suggest that pan-
PPAR agonists that include a component of
PPAR beta/delta activation might offset some of the
weight gain issues seen with selective
PPAR gamma agonists, as was demonstrated by
bezafibrate studies. Suggestively, on the whole body level all PPARs acting as one orchestra and balanced pan-
PPAR activation seems as an especially attractive pharmacological goal. Conceptually, combined
PPAR gamma and alpha action can target simultaneously
insulin resistance and atherogenic
dyslipidemia, whereas
PPAR beta/delta properties may prevent the development of
overweight.
Bezafibrate, as all
fibrates, significantly reduced plasma
triglycerides and increased HDL-C level (but considerably stronger than other major
fibrates).
Bezafibrate significantly decreased prevalence of small, dense
low density lipoproteins particles, remnants, induced
atherosclerotic plaque regression in thoracic and abdominal aorta and improved endothelial function. In addition,
bezafibrate has important
fibrinogen-related properties and anti-inflammatory effects. In clinical trials
bezafibrate was highly effective for cardiovascular risk reduction in patients with
metabolic syndrome and atherogenic
dyslipidemia. The principal differences between
bezafibrate and other
fibrates are related to effects on
glucose level and
insulin resistance.
Bezafibrate decreases
blood glucose level, HbA1C,
insulin resistance and reduces the incidence of T2DM compared to placebo or other
fibrates. Currently
statins are the cornerstone of the treatment and prevention of
cardiovascular diseases related to
atherosclerosis. However, despite the increasing use of
statins as monotherapy for
low density lipoprotein- cholesterol (
LDL-C) reduction, a significant residual cardiovascular risk is still presented in patients with atherogenic
dyslipidemia and
insulin resistance, which is typical for T2DM and
metabolic syndrome. Recently, concerns were raised regarding the development of diabetes in
statin-treated patients. Combined
bezafibrate/
statin therapy is more effective in achieving a comprehensive
lipid control and residual cardiovascular risk reduction. Based on the beneficial effects of pan-
PPAR agonist
bezafibrate on
glucose metabolism and prevention of new-onset diabetes, one could expect a neutralization of the adverse pro-diabetic effect of
statins using the strategy of a combined
statin/
fibrate therapy.