There are three
peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated
PPAR alpha,
PPAR gamma and
PPAR beta/delta.
PPAR alpha activation increases
high density lipoprotein (
HDL) cholesterol synthesis, stimulates "reverse"
cholesterol transport and reduces
triglycerides.
PPAR gamma activation results in
insulin sensitization and
antidiabetic action. Until recently, the
biological role of
PPAR beta/delta remained unclear. However, treatment of obese animals by specific
PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with
PPAR gamma and alpha agonists may potentially improve
insulin resistance and alleviate atherogenic
dyslipidemia, whereas
PPAR delta properties may prevent the development of
overweight which typically accompanies "pure"
PPAR gamma ligands. The new generation of dual-action PPARs--the glitazars, which target
PPAR-gamma and
PPAR-alpha (like
muraglitazar and
tesaglitazar) are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including
ragaglitazar and
farglitazar). The old and well known
lipid-lowering
fibric acid derivative
bezafibrate is the first clinically tested pan--(alpha, beta/delta, gamma)
PPAR activator. It is the only pan-
PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore,
bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-
PPAR ligand.
Bezafibrate leads to considerable raising of
HDL cholesterol and reduces
triglycerides, improves
insulin sensitivity and reduces
blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of
metabolic syndrome. Clinical evidences obtained from
bezafibrate-based studies strongly support the concept of pan-
PPAR therapeutic approach to conditions which comprise the
metabolic syndrome. However, from a biochemical point of view,
bezafibrate is a
PPAR ligand with a relatively low potency. More powerful new compounds with pan-
PPAR activity and proven long-term safety should be highly effective in a clinical setting of patients with coexisting relevant
lipid and
glucose metabolism disorders.