Lipid lowering with fibric acid derivatives
Lipid altering agents encompass several classes of drugs that include HMG CoA
reductase inhibitors or statins, fibric acid derivatives, bile acid
sequestrants,
nicotinic
acid, and
probucol.
These drugs differ with respect to mechanism of action and to the degree and
type of lipid lowering. Thus, the indications for a particular drug is
influenced by the underlying lipid abnormality. Conventional dosing regimens
and common adverse reactions are described in Table 1 (
show
table 1), the range of expected changes in the lipid profile are listed in
Table 2 (
show
table 2), and the average monthly cost is depicted in Table 3 (
show
table 3).
The treatment of individual lipid disturbances and their efficacy in improving
patient outcome with both primary and particularly secondary prevention of
coronary heart disease (CHD) are discussed separately. (
See
"Clinical trials of cholesterol lowering for primary prevention of
coronary heart disease" and
see
"Clinical trials of cholesterol lowering in patients with coronary heart
disease-I").
The mechanisms of benefit seen with lipid-lowering are incompletely
understood. Regression of atherosclerosis occurs in only a minority of
patients; furthermore, the benefit of lipid lowering is seen in as little as
six months, before significant regression could occur. Thus, other factors
must contribute; these include plaque stabilization, reversal of endothelial
dysfunction, and decreased thrombogenicity. (
See
"Mechanisms of benefit of lipid lowering in patients with coronary heart
disease").
This card will review the characteristics and efficacy of the fibric acid
derivatives. Other lipid lowering drugs are discussed separately.
FIBRATES ！ Three fibrates are currently
available in the United States:
gemfibrozil,
clofibrate,
and
fenofibrate.
Clofibrate
should not be used since it has been associated with cholangiocarcinoma and
other gastrointestinal cancers [
1].
Other fibrates that are available worldwide include bezafibrate and
ciprofibrate.
Efficacy ！ The major effects of the
fibrates are to lower plasma triglyceride and raise HDL levels [
2,3].
They produce a prominent (35 to 50 percent) reduction in plasma triglyceride
levels by two mechanisms (
show
figure 1 and
show
table 2):
• Reduced hepatic secretion of VLDL.
• Facilitated clearance of triglyceride-enriched
lipoproteins by stimulating lipoprotein lipase activity, an effect that may be
mediated by downregulation of apolipoprotein C-III gene expression at the
transcriptional level [
3,4].
(
See
"Lipoprotein classification; metabolism; and role in atherosclerosis").
Three mechanisms have been described for the 15 to 25 percent elevation in HDL
produced by these agents:
• Direct stimulation of the synthesis of
apolipoprotein A-I (an apoprotein associated with HDL). The direct effect of
gemfibrozil
on apo A-I has been shown to result from stabilization of apo A-I mRNA
transcripts, leading to translation and secretion of more apo A-I containing
HDL particles which mediate reverse cholesterol transport [
3,5,6].
• Increased transfer of apo A-I and other surface
components in conjunction with diminished cholesterol transfer from HDL to
VLDL.
• Less inhibition by VLDL (due to the reduction in
concentration) on hepatic apo A-I synthesis.
The fibrates have a variable effect of Lp(a) levels. In one study, for
example, bezafibrate reduced Lp(a) levels by approximately 26 percent overall
and by 39 percent in patients with Lp(a) levels above 30 mg/dL [
7].
In another report, the effect of
gemfibrozil
on Lp(a) levels varied with the lipid disorder: a 17 percent reduction in
patients with type IIa hyperlipoproteinemia (p = 0.04) versus no change in
those with type IIb hyperlipoproteinemia [
8].
In patients with type IIb hyperlipoproteinemia, Lp(a) forms complexes with
VLDL. These complexes are cleared by remnant receptors causing a net fall in
Lp(a) levels. Since fibrates reduce VLDL (enhanced clearance, decreased
production), less Lp(a) is cleared via Lp(a)/VLDL complexes and plasma Lp(a)
levels may rise. An additional possible mechanism for the lack of Lp(a)
lowering with fibrates in this setting is the reduced need for VLDL-associated
apo B, resulting in more substrate availability for Lp(a) formation.
The newer fibric acid derivatives appear to differ from
gemfibrozil
in their effect on the serum fibrinogen concentration. They lower fibrinogen
levels while
gemfibrozil
has no effect.
Gemfibrozil
may, however, normalize impaired endogenous fibrinolysis by reducing levels of
plasminogen activator inhibitor type-1 in patients with hypertriglyceridemia
or (possibly) non-insulin-dependent diabetes [
9,10].
Uses
Gemfibrozil ！
Gemfibrozil
and other fibrates are effective for the treatment of hypertriglyceridemia and
combined hyperlipidemia with or without hypoalphalipoproteinemia [
2].
At a dose of 600 mg twice daily,
gemfibrozil
increases HDL cholesterol levels by an average of 11 percent. However, the
Helsinki Heart Study showed a more prominent elevation in HDL cholesterol in
the lower range of plasma HDL levels (ie, in those at greatest cardiovascular
risk) [
11].
Subgroup analysis of the Helsinki Heart Study found that
gemfibrozil
was particularly effective in preventing heart disease in patients with high
triglyceride levels (>202 mg/dL) plus either low HDL cholesterol (<42
mg/dL [1.1 mmol/L]) or a high LDL/HDL cholesterol ratio (>5.0).
One unexpected outcome of this and some other trials has been the association
of lipid lowering with an enhanced risk of noncardiac death, particularly due
to accidents, violence, or suicide [
12].
However, more recent larger trials (primarily conducted with an HMG CoA
reductase inhibitor) have been unable to confirm any relation between lowering
of cholesterol and an increase in noncardiovascular deaths (due, for example,
to suicide) [
13,14].
Fenofibrate ！
Fenofibrate
can be prescribed as a micronized formulation (one 200 mg capsule) or as three
67 mg capsules (United States) [
15].
Unlike other fibric acid derivatives, the metabolic actions of
fenofibrate
involve inhibition of peroxisome proliferator-activator receptors (PPAR) [
16]. PPAR
is found in tissues with high rates of fatty acid catabolism where it is
involved in the oxidation of fatty acids.
Fenofibrate
is approved for triglyceride-lowering in subjects with types IV and V
hyperlipoproteinemia. One study randomized 84 combined hyperlipidemia subjects
to
fenofibrate
or
atorvastatin
(10 mg/day) [
17].
Fenofibrate
was more effective in reducing concentrations of triglycerides and VLDL-cholesterol
while
atorvastatin
was more effective in lowering LDL-cholesterol, apo B, and total cholesterol.
An important drug interaction is that
fenofibrate
increases the clearance of
cyclosporine.
In one series of 43 heart transplant recipients, for example,
fenofibrate
therapy led to a 30 percent reduction in
cyclosporine
levels [
18].
Five of these patients had an episode of acute rejection that was associated
with decrease in
cyclosporine
levels on the visit before the episode. A small elevation in the plasma
creatinine concentration of 0.34 mg/dL (30 µmol/L), which did not become
apparent for at least six months, was also noted.
Bezafibrate ！ Bezafibrate can
be prescribed in dosages of 200 mg. three times daily or a sustained-release
daily dose of 400 mg. daily [
19].
Fibrates are primarily excreted by the kidneys; therefore, the dosage and
dosing interval should be reduced in patients with renal insufficiency to
avoid myositis. The dosing of bezafibrate, for example, should be reduced
according to this schedule:
Creatinine clearance
40 to 60 mL/min - 400 mg/day
15 to 40 mL/min - 200 mg daily or every other
day
Dialysis - 200 mg every third day
Bezafibrate, like other fibrates, interacts with
warfarin.
As a result, the
warfarin
dose should be reduced by 30 percent in patients treated with this drug.
