Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00055
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Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: August 2007
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Bibliographic ID: UF00087345
Volume ID: VID00055
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Joseph J. Fierro, Pharm.D. Candidate

The fibric acid derivatives, also known as
fibrates, are well established as effective agents for
managing dyslipidemia, in particular elevated con-
centrations of triglyceride-rich very-low-density
lipoprotein (VLDL) and VLDL remnants and low
levels of high-density lipoprotein cholesterol (HDL-
C) that are typically associated with the dyslipidemia
characteristic of type 2 diabetes and the metabolic
syndrome. There are currently two fibrates available
in the United States: gemfibrozil (Lopid) and feno-
fibrate (Antara, Lofibra, TriCor, Triglid). Clofi-
brate has been discontinued in the United States
since it has been associated with cholangiocarcinoma
and other gastrointestinal cancers.' Other fibrates
that are available worldwide include bezafibrate and
Fibrates are indicated for the treatment of hy-
percholesterolemia, hypertriglyceridemia, and as ad-
junctive therapy to diet to reduce elevated total cho-
lesterol, low-density lipoprotein cholesterol (LDL-
C), triglycerides, and apolipoprotein-B (apo-B), and
to increase HDL-C in adult patients with primary
hypercholesterolemia or mixed dyslipidemia.2 The
use of fibric acid derivatives has decreased over the
years because of unimpressive results in major clini-
cal trials, safety concerns, and the emergence of
HMG-CoA reductase inhibitors, more commonly
known as stations. While stations are considered first-

line therapy for dyslipidemia based on their efficacy
in reducing levels of LDL-C, they exhibit only mod-
est effects by decreasing triglycerides about 15-35%
and increasing HDL up to 15%.3
The safety and efficacy of fibrates have been
reviewed in six major clinical trials during the past
30 years. The results have generated mixed findings
when evaluating overall mortality, cardiovascular
events, and adverse effects. The inconsistent out-
comes may be a result of differences among individ-
ual fibrates and highly varied study populations. In
this article, the pharmacology of the fibrates is dis-
cussed along with evaluating their role in the primary
and secondary prevention of coronary heart disease

Mechanism of Action
Fibrates have a complex mechanism of ac-
tion, involving several steps in the metabolism of
lipoproteins. Primarily, fibrates affect the perox-
isome proliferator activated receptor (PPAR)-ac
(Table 1).4 The PPARs are a group of nuclear recep-
tors predominantly expressed in tissues, such as the
liver, kidney, heart and muscle, that metabolize fatty
acids. On activation by binding of the fibrate,
PPAR-a binds as heterodimers with a retinoid X re-
ceptor (RXR), which then recognizes and binds to


l I




Volume 22, Issue 11 August 2007


specific PPAR-a response elements leading to ex-
pression modulation of the target genes.5In particu-
lar, the activity of lipoprotein lipase is increased and
synthesis of apoC-III is decreased, which both en-
hance the clearance of circulating triglyceride-rich
lipoproteins.6 PPAR-a activation regulates gene ex-
pression involved in metabolic pathways including
lipid metabolism, thereby reducing triglyceride con-
centrations and increasing HDL concentrations.
Fatty acid oxidation in the liver is also increased re-
sulting in decreased synthesis of VLDL.7 In addi-
tion, fibrates promote a shift towards producing lar-
ger, more buoyant LDL particles that are less suscep-
tible to oxidation and have higher affinity for the
LDL receptor.8 Fibrates also appear to stimulate re-
verse cholesterol transport by modulating macro-
phage cholesterol efflux, cholesterol transport, and
bile acid synthesis, thereby enhancing HDL concen-
The described mechanisms of action generate
significant decreases in plasma triglyceride concen-
trations ranging from 20-50% and elevations in HDL
concentrations ranging from 10-35%.8 Fibrates have
varying effects on LDL concentrations. Among pa-
tients with increased LDL concentrations, modest
reductions of 5-20% have been observed; however,
fibrates can increase LDL concentrations if accompa-
nied by hypertriglyceridemia, secondary to the en-
hanced lypolysis of VLDL by lipoprotein lipase.5
Therefore, fibrates are primarily used for the treat-
ment of hypertriglyceridemia and atherogenic dyslip-
idemia (i.e. elevated plasma triglyceride concentra-
tions, small dense LDL particles, low HDL concen-

Table 1: Effects of PPAR-a stimulation by fibrates10

ApoAI mRNA transcription stabilization

1 apoAI and apoAII -* HDL particle size number

JapoCIII-- TG T LDL size

T LPL TG T HDL cholesterol

1 LPL improved post-prandial lipidemia

T hepatic VLDL and apoB degradation

I VLDL and apoB production
Apo apolipoprotein; HDL= high-density lipoprotein; LDL= low-density
lipoprotein; LPL= lipoprotein lipase; mRNA= messenger RNA; TG= triglyc-
erides; VLDL= very-low-density lipoprotein

Major Trials of Fibrate Therapy

The safety and efficacy of fibrates have been as-
sessed in six major outcome studies during the past
30 years (Table 2).

Coronary Drug Project
The Coronary Drug Project (CDP) was one of
the earliest lipid trials published in 1975.12 It was de-
signed to determine safety and efficacy of several
antihyperlipidemic drugs in preventing a recurrent
CHD event among men with a history of myocardial
infarction. One of the treatment groups, in which pa-
tients were randomly assigned to receive clofibrate,
continued until the end of this approximately 5-year
study. The rate of CHD events was reduced 9% in
the clofibrate group, but the difference between
groups was not statistically significant. The study
brought up concern regarding clofibrate because of a
lack of effectiveness on overall mortality and a sig-
nificantly higher rate of cholelithiasis compared with
placebo. The authors concluded that the CDP results
provided no evidence with which to suggest the use
of clofibrate among men with CHD.

World Health Organization Study
In 1978, the results from the World Health
Organization (WHO) cooperative trial in the primary
prevention of ischemic heart disease using clofibrate
generated more doubt regarding the use of fibrates.13
Men, ages ranged from 30-59 years with hypercho-
lesterolemia without cardiovascular disease, were
randomly assigned to take clofibrate or placebo and
were followed for an average of 5.3 years. The clofi-
brate group had a 25% reduction (p<0.05) in nonfatal
myocardial infarction compared to placebo; how-
ever, overall mortality and the rate of cholelithiasis
and cholecystectomy were significantly higher with
clofibrate than placebo. Patients receiving clofibrate
had a 9% decrease in total cholesterol concentra-
tions, which was less than the expected 15% reduc-
tion. The higher mortality rates associated with
clofibrate were partly due to a higher rate of malig-
nant neoplasms of the liver, gallbladder, and intes-
tines; however, mortality rates among the clofibrate
group for cancer were similar to the official mortality
statistics for individuals from the same area. The au-
thors believed the increased mortality may have been
exaggerated because of unexpectedly low death rates
among subjects in the control group. Patients gaining

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Table 2: Key Findings from Major Trials of Fibrate Therapy"
Trl Duration Drug and Lipid changes
Trial N Population Outcomes
(yrs) daily dose (%)
CHD: 9% (p = 0.12)
CDP 5 3892 Men, 2 Clofibrate 1 TC: 1 8% Total mortality: no change
prevention TGs: 1 25% T cholelithiasis and cholecystec-
Nonfatal MI: 1 25% (p < 0.05)
WHO 5.3 10,627 Men, 1Clofibrate 1.6g TC Total mortality: T with clofibrate
prevention T cholelithiasis and cholecystec-
tomy with clofibrate
TC: 11% CHD 34%
THHS 5 4081 Men, 1 Gemfibrozil LDL: 1 10% 3o
HHS 5 4081 Nonfatal MI: 1, 37%
prevention 1200mg TGs: 1 43% T l m n
HDL:10% Total mortality: no change
HDL: 1 10%
TC: 1 4%
TC: 4 CHD death and nonfatal MI: ,
VA-HIT 5.1 2531 Men, 2' Gemfibrozil LDL: 0% 22%
prevention 1200mg TGs: 1 31% l m
HDL: 1 6%o Total mortality: 11%0(NS)
HDL: T 6%
TC: 1 4.5%
Men and TC: 4% Fatal and nonfatal MI and sudden
Bezafibrate LDL: 1, 6.5% d 9 (
BIP 6.2 3090 women, 2 B : 16 death: 9% (NS)
prevention HDL T : t 18% Total mortality: no change
HDL: T 18%
11 CHD death and nonfatal MI: [
TC: 1 11%
Men and Fenofibrate LDL: 12% (NS)
FIELD 5 9795 women with T 12 Total mortality: T 19% with fenofi-
DM mg HL % brate (NS)
HDL: t 5%
Total cardiovascular events: I 11%
1 = decrease; 1 = increase; N = number of patients; 1 = primary; 2 = secondary; DM = diabetes mellitus; CDP = Coronary Drug Project; CHD= coronary heart
disease, NS = not statistically significant; WHO = World Health Organization; MI = myocardial infarction; HHS = Helsinki Heart Study; TC = total cholesterol; TGs
=triglycerides; LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol; VA-HIT = Veterans Affairs HDL Intervention Trial; BIP =
Bezafibrate Infarction Prevention; FIELD = Fenofibrate Intervention and Event Lowering in Diabetes

the most benefit from clofibrate had higher baseline
cholesterol concentrations and greater reductions in
total cholesterol, or experienced a substantial reduc-
tion in serum cholesterol levels with co-morbid car-
diovascular risk factors. Nevertheless, the results of
the WHO trial and CDP produced substantial doubt
concerning clofibrate, and subsequent prescribing of
the agent decreased dramatically.

Helsinki Heart Study
The Helsinki Heart Study (HHS),14 a double-
blind, placebo-controlled study including more then
4,000 men at moderate risk of CHD treated with
gemfibrozil (1,200 mg/day), was published in 1987.
It showed an 11% decrease in LDL-C, a 35% de-
crease in triglycerides, and an 11% increase in HDL-
C compared with placebo. These changes were asso-
ciated with a 34% reduction (95% CI, 8.2-52.6%;
p<0.02) in major coronary events at five years, as
well as a 37% reduction (p<0.05) in non-fatal myo-
cardial infarction in men free of CHD. There was no

significant difference in overall mortality between
the two groups. The HHS also provided data regard-
ing the safety of fibrates, as cases of newly diag-
nosed cancer and the rates of cholecystectomy were
not different between the groups.

Veterans Affairs High-Density Lipoprotein Choles-
terol Intervention Trial
The Veterans Affairs High-Density Lipopro-
tein Cholesterol Intervention Trial (VA-HIT) was
another randomized, placebo-controlled trial using
gemfibrozil.5 Men with a history of CHD and low
HDL levels were assigned randomly to receive gem-
fibrozil or placebo for 5 years. Gemfibrozil gener-
ated significant changes in HDL and plasma triglyc-
eride concentrations compared to placebo, whereas
LDL concentrations showed no significant differ-
ence. Patients in the treatment group were 22% (95%
CI, 7-35%; p=0.006) less likely to experience CHD
death or a nonfatal myocardial infarction compared
to those in the control group. Though not designed to

PharmaNote Volume 22, Issue 11 August 2007

Volume 22, Issue 11 August 2007


assess overall mortality, the investigators reviewed
the number of deaths and reported an 11% (95% CI,
-8 to 27%; p = 0.23) reduction in mortality with gem-
fibrozil compared with placebo. Further analyses of
VA-HIT data proposed that the major reason for
clinical events being reduced was increased HDL
levels from gemfibrozil.16 Like the HHS, VA-HIT
generated favorable results regarding long-term
safety of fibrates because the incidence of newly di-
agnosed cancer and gallbladder disease between
treatment and control groups was no different.

Bezafibrate Infarction Prevention Study
The Bezafibrate Infarction Prevention (BIP)
study was another randomized, placebo-controlled
trial studying the effects of bezafibrate, a fibrate not
available in the United States, among men and
women with CHD.17 Bezafibrate therapy demon-
strated significant reductions in triglyceride and LDL
concentrations and fibrinogen while elevating HDL
levels. When the study was completed, bezafibrate
was associated with a 9% reduction (p=0.26) in fatal
and nonfatal myocardial infarction and sudden death.
Overall mortality rates and frequency of newly diag-
nosed cancer were similar among the groups, show-
ing bezafibrate to be safe agent among adults with
CHD, but it had no significant effect on the fre-
quency of major coronary events.

Fenofibrate Intervention and Event Lowering in Dia-
betes Study
Published recently, the Fenofibrate Interven-
tion and Event Lowering in Diabetes (FIELD) study
intended to offer additional information on the use
and safety of fibrates in diabetic patients.l* Men and
women not receiving station therapy at the beginning
of the trial were assigned randomly to fenofibrate or
placebo for 5 years. All participants had type 2 dia-
betes mellitus, and 37% of patients experienced a
cardiovascular event in the past. Treatment with fen-
ofibrate resulted in significant reductions in total
cholesterol levels, triglyceride concentrations, and
LDL levels compared with the control group. Fenofi-
brate produced a 5% increase in HDL early in the
study; however, this decreased to only 2% by the end
of the study. Patients taking fenofibrate had an 11%
reduction (95% CI, -5 to 25%; p=0.16) in coronary
events (CHD death and nonfatal myocardial infarc-
tion), but also a nonsignificant increase in overall
mortality (11%, 95% CI, -5 to 29%; p = 0.18), com-

pared with the control group. The lower rate of coro-
nary events was due primarily to the decrease in non-
fatal myocardial infarction. Also, a reduction in total
cardiovascular events was observed with the fenofi-
brate group. Compared with the placebo group, those
in the treatment group were more likely to experi-
ence pancreatitis and pulmonary embolism.18 The
results of the FIELD study were much anticipated in
hopes of determining the role fibrates play in the
treatment of cardiovascular disease, but unfortu-
nately they did not live up to that expectation. With
only modest reductions in cardiovascular events and
no significant changes in overall mortality, the
FIELD study hardly helped define the role of fi-

Discussion Regarding Mixed Results
Although fibrates do not provide significant
LDL reductions, they do increase HDL levels and
reduce triglyceride concentrations.19 In addition, the
fibrates generate improvements in many of the
emerging risk factors, including CRP level, fibrino-
gen level, and small dense LDL particles.20 The gen-
eral metabolic effects of fibrates would suggest that
they are the best agents for individuals with type 2
diabetes mellitus or metabolic syndrome. The fol-
lowing key points address the primary reasons why
the major fibrate studies have provided varied re-
Firstly, a major possibility for mixed results
may be due to the diverse study populations in fi-
brate trials.1l Although data from fibrate trials are not
identical, two groups that appear to receive the most
benefit from fibrates are patients with mixed dyslipi-
demia (low HDL levels and elevated plasma triglyc-
eride concentrations) and/or impaired glucose ho-
meostasis (i.e., type 2 diabetes mellitus, prediabetes
or metabolic syndrome).2122 When reviewing base-
line lipid levels of study participants, it is apparent
that a fibrate was not the best selection as a lipid
lowering agent.17 The most common lipid abnormali-
ties of the study subjects were elevated LDL and to-
tal cholesterol levels, but at the time of the earlier
studies, drug therapy for lowering LDL levels was
limited primarily to bile acid resins and niacin. Also,
most of the studies had limited numbers of patients
with diabetes mellitus. Recruiting more patients with
mixed dyslipidemia and glucose impairment would
provide more positive findings since fibrates seem to
be more effective in that patient population. Lastly,

PharmaNote Volume 22, Issue 11 August 2007

Volume 22, Issue 11 August 2007


fibric acid derivatives have shown to reduce some of
the newer cardiovascular risk factors that are
strongly associated with mixed dyslipidemia and
metabolic syndrome.23 This may help explain why
fibrates have generally provided greater efficacy at
reducing cardiovascular events among these popula-
tions in post hoc analyses.
Although post hoc data from fibrate trials
suggest greater reductions in clinical events among
patients with metabolic syndrome or type 2 diabetes
mellitus, results from the FIELD study did not com-
pletely support these findings as the reductions in
cardiovascular events were modest compared with
post hoc results of previous fibrate studies. 11 Several
reasons may explain why the patients did not experi-
ence greater benefit with fenofibrate. First, a signifi-
cantly greater number of patients in the control group
began other lipid-modifying agents (primarily stat-
ins) potentially masking the effects of fibrate ther-
apy. Second, baseline lipid levels were not the most
advantageous for using fibrate therapy because indi-
viduals appear to have a more favorable clinical re-
sponse when baseline plasma triglyceride concentra-
tions exceed 200 mg/dl and the HDL concentration is
less than 40 mg/dl. Subgroup analysis of the FIELD
study showed patients with low HDL levels (< 40
mg/dl for men and < 50 mg/dl for women) or plasma
triglyceride concentrations of 150 mg/dl or greater
experienced a decreased rate of cardiovascular
events; however, subjects meeting the criteria for
metabolic syndrome experienced more clinical
events compared with those without metabolic syn-
drome. 1 Further analyses of these subpopulations
are needed to clarify the inconsistent results.
Slight differences among individual fibric
acid derivatives may have also added to inconsis-
tency in safety and efficacy reported in clinical tri-
als." Gemfibrozil has provided the most impressive
data at decreasing clinical events. However, drug
interactions, especially with concomitant station use,
and potential for higher rates of myopathies may
limit use in clinical practice. Fenofibrate seems to be
more effective than gemfibrozil at positively altering
lipid parameters and does not significantly affect
station metabolism; however, the FIELD study did not
provide the robust evidence required to indicate ex-
clusive use of this agent.24 In addition, safety con-
cerns regarding slight, but significant increases in
pancreatitis and pulmonary embolism in recent trials
suggest a need for health professionals to be aware of

these possible adverse effects. A class effect cannot
be ruled out since the rates of pulmonary embolism
and pancreatitis were not reported in most other ma-
jor fibrate trials.

The exact role of fibric acid derivatives in
lipid lowering therapy and prevention of CHD is still
unclear. Early studies involving clofibrate were dis-
appointing because of only modest reductions in
CHD events and considerable safety concerns. The
HHS, which used gemfibrozil, provided reassurance
in terms of long-term safety of fibrates and demon-
strated reductions in CHD events, but did not reduce
overall mortality. Further analyses of fibrate trials
evaluated patients with lipid profiles more conducive
to the effects of fibric acid derivatives. The positive
results of these studies suggest a potential value of
fibrates when used in appropriate populations. With
the publication of the FIELD study came expecta-
tions of solidifying a larger market for fibrates in
treatment of cardiovascular disease; however, due to
mixed results, further research is needed to better
determine the best targeted usage of these agents.
Results of recent ongoing trials, such as the Action to
Control Cardiovascular Risk in Diabetes (ACCORD)
trial, may determine if this class will once again play
a greater role in the management of dyslipidemia and
the prevention of coronary heart disease.

1. WHO cooperative trial on primary prevention of
ischemic heart disease with clofibrate to lower
serum cholesterol: final mortality follow-up. Re-
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Nov, 2004
3. Executive Summary of the Third Report of the
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ment of high blood pressure in adults (Adult
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4. Staels B, Dallongeville J, Auwerx J, Schoonjans
K, et al. Mechanism of action of fibrates on lipid
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5. Fazio S, Linton MF. The role of fibrates in man-
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6: 148-57
6. Expert Panel on Detection, Evaluation, and
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10. Despres JP, Lemieux I, Robins SJ. Role of fibric
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The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

Shawn Anderson Assistant Editor

IP a Vllum 2 sue1 uut 2007 I

Volume 22, Issue 11 August 2007


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