Introduction
Fenofibrate, a Third-Generation Fibric Acid Derivative
W. VIRGIL BROWN, M.D.
uring the past 20 years, fibric acid derivatives have
D been the major drugs used in the treatment of hy-
perlipidemia. Clofibrate (Atromid-S) and, more recently,
gemfibrozil (Lopid) have been available in the United
States with Food and Drug Administration approval as
prescription agents for the reduction of elevated plasma
triglyceride levels. Neither has proved to be generally use-
ful ‘for first-line drug treatment of hypercholesterolemia al-
though it is well-known that cholesterol reductions do
occur in some patients given either one of these agents.
Enthusiasm for their use has been muted by the lack of
consistent reductions of low-density lipoproteins, the
major plasma lipoprotein carrying cholesterol. Also, the
failure of clinical trials to demonstrate clear benefits of
therapy with these agents has reduced their prescription
by physicians. This may be changed by the impending
report of the Helsinki Heart Study, a long-term random-
ized trial of gemfibrozil versus placebo in the primary pre-
vention of coronary heart disease.
The report of the World Health Organization coopera-
tive trial of clofibrate in 1978 resulted in a marked decline
in the prescribing of this agent [l]. Although the group
receiving clofibrate experienced a reduction of nonfatal
coronary heart disease in association with a 9 percent
reduction in blood cholesterol levels compared with a pla-
cebo-treated control group, the sum of all cardiovascular
events including cardiac mortality was not reduced signifi-
cantly. In fact, a higher total mortality was observed with
clofibrate treatment. This was not attributable to a single
cause, but death related to cholecystectomy was a major
contributor to this excess mortality. Second, the appear-
ance of a trend toward an excessive total cancer rate pro-
duced a strong negative reaction on the part of medical
practitioners and their patients. This higher cancer inci-
dence in the treated group was not related to the degree
of cholesterol reduction and has subsequently bisap-
peared as the trial cohort has continued to be monitored.
Nevertheless, the stigma from this initial report continues
to color attitudes about the use of this drug.
From the Department of Medicine, Mount Sinai Hospital,
be addressed to Dr. W. Virgil Brown, Hyman Research
Street, Washington, D. C. 20010.
November 27, 1987
ln 1982, gemfibrozil was released for use in the United
States and today is more commonly used than clofibrate.
The triglyceride reduction achieved with gemfibrozil ap-
pears to be similar to that with clofibrate, but success in
the reduction of low-density lipoprotein cholesterol is no
greater or more frequent. Gemfibrozil has been reported
to produce a significant and consistent elevation of high-
density lipoprotein cholesterol, which is greater than that
with clofibrate, and this has been viewed as an advantage
[2]. Although higher levels of high-density lipoprotein cho-
lesterol are associated with reduced incidence of coronary
heart disease, no studies have as yet proved the benefit of
raising high-density lipoprotein cholesterol levets with
drug therapy [3]. The Helsinki Heart Study may give addi-
tional information on this issue. The reported side effects
with clofibrate are given in Table I. However, a preliminary
report from The Helsinki Study indicates no increment in
cholecystitis during the first three years and eight months
of monitoring therapy with gemfibrozil [4]. “
In Europe, a series of newer fibric acid derivatives have
been developed and clinical trials haye been completed
for demonstration of short-term safety and efficacy. As a
result, the prescription use of such agents as fenofibrate
(Lipidil), bezafibrate, and ciprofibrate is common. Two
important differences exist between these third-genera-
tion agents and earlier members of this therapeutic class:
greater potency, since lower doses are required to pro-
duce a given response, and greater reductions in Iow-
density lipoprotein cholesterol levels. These additional
benefits are achieved while preserving the increased
high-density lipoprotein cholesterol levels produced ‘by
some older agents.
In fact, the third-generation agent, fenoftbrate, has been
available in the pharmacies of France and other European
and Middle Eastern nations for over 10 years. Fenofibrate
is one of the most commonly prescribed lipid-lowering
agents in the world, with an estimated six million patient-
years of use in treatment. This,drug has been used in
clinical trials in the United States for several years and
New York, New York. Requests for reprints should
Building, The Medlantic Foundation, 108 Irving
The American dournal of Medicine Volume 83 (suppl 58) 1
SYMPOSIUM ON FENOFIBRATE-BROWN

TABLE I Reported Side Effects of Fibric Acid cent for low-density lipoprotein cholesterol produced by
Derivatives fenofibrate in this recent study [4] is certainly worthy of
attention. It is for this reason that a symposium was held
l Gastrointestinal to review other relevant data on a variety of topics includ-
Nausea, eructation, flatulence, diarrhea, abdominal pain ing the pharmacodynamics, mechanisms of action, effi-
l Skin
Rash, urticaria, hair loss, increased sweating cacy; and side effects of fenofibrate as compared with
l Musculoskeletal other fibric acid derivatives. Several of the presentations
Myalgias, elevated CPK and SGOT at this symposium have been compiled for this supple-
l Hepatic ment. We believe that these will be useful to the physician
Lithogenic bile, gall stones,’ elevated SGPT and SGOT
seeking to broaden his familiarity with the agents that are
l Psychoneurologic
Dizziness, fatigue, headache, insomnia, impotence currently available and those soon to be available for the
l Cardiovascular management of hypercholesterolemia.
Atrial and ventricular arrhythmias* Currently, our choice of pharmacologic agents is lim-
l Hematologic ited. Although the bile acid binding sequestrants such as
Leukopenia, anemia
l Drug interactions cholestyramine (Questran) and colestipol (Colestid) are
Potentiate coumarins safe and effective, they require some patient involvement
in preparation and are not readily accepted oy all patients.
CPK = creatine phosphokinase; SGOT = serum glutamic oxaloa-
cetic transaminase; SGPT = serum glutamic pyruvic transaminase. Niacin is also very effective and has been associated with
*Documented only for clofibrate in the Coronary Drug Project and the reduction in mortality in the long-term monitoring of
World Health Organization Study. treated patients from the Coronary Drug Project [7]. How-
ever, this drug has numerous side effects that reduce its
shows promise as having certain advantages over clofi- usefulness. Probucol (Lorelco) is relatively inexpensive
brate and gemfibrozil. In a recent multicenter study [4,5] but is erratic in its efficacy in lowering low-density lipopro-
using a double-blinded, randomized, placebo-controlled tein cholesterol levels, it frequently lowers high-density
design, fenofibrate was demonstrated to produce a very lipoprotein cholesterol levels, and it has not been ade-
significant reduction in low-density lipoprotein cholesterol quately studied in large clinical trials to demonstrate either
levels in those patients with elevated low-density lipopro- its value in preventing coronary heart disease or the less
tein cholesterol and normal triglyceride levels (type II A) common side effects that may require years to uncover.
as well as those with elevated low-density lipoprotein cho- Clofibrate and gemfibrozil have not been generally useful
lesterol and elevated triglyceride levels (type II B). as first-line drug therapy for cholesterol reduction, though
The relationship of the serum low-density lipoprotein they are approved for use by patients in whom other
cholesterol level and the incidence of myocardial infarc- agents have failed. Finally, we must be cautious in the use
tion and other manifestations of coronary heart disease is of the newer agents that act by inhibiting cholesterol syn-
now well established. For men with low-density lipoprotein thesis through their direct interaction with hydroxymethyl
cholesterol levels exceeding 190 mgidl, therapy with the glutaryl coenzyme A reductase, the rate-limiting enzyme
drug cholestyramine (Questran) produced a 19 percent in cholesterol synthesis. These agents, such as lovastatin
reduction in the sum of major coronary events including (Mevacor) and eptastatin (also known as pravastatin),
sudden cardiac death and first myocardial infarctions [6]. show great promise, but only a few years of observation
This was associated with an average serum cholesterol are available and the possibility of serious side effects
reduction of less than 9 percent and low-density lipopro- appearing after longer use in larger numbers of patients
tein cholesterol reduction of approximately 11 percent as must be kept in mind. In this setting, availability of another
compared with the placebo-treated control group. In this effective drug with a record of long-term usage in reducing
context, the average reduction of approximately 20 per- low-density lipoprotein cholesterol would be welcome.

REFERENCES
1. Helsinki Heart Study Ethical Committee: Safety as a factor in tion 1984; 70 (1): 153A-205A.
lipid-regulating primary prevention drug trials: The Helsinki 5. Brown WV, Dujovne CA, Farquhar JW, et al: Effects of fenofibrate
Heart Study Interim Report. In: Wood C, ed. Further progress on plasma lipids. Arteriosclerosis 1988; 8: 708-708.
with gemfibrozil. Royal Society Medical Services International 6. Knopp RH, Brown WV, Dujovne CA, et al: Effects of fenofibrate
Congress and Symposium Series 87, 1986. on plasma lipoproteins in hypercholesterolemia and combined
2. Committee of Principal Investigators: A cooperative trial in the hyperlipidemia. Am J Med 1987; 83 (suppl 58): 50-59.
primary prevention of ischaemic heart disease using clofibrate. 7. Lipid Research Clinics Program: The Lipid Research Clinics Cor-
Br Heart J 1978; 10: 1069-1118. onary Primary Prevention Trial Results. I. Reduction in inci-
3. Hall MJ, Nelson LM, Russell RL, et al: A comparison of the effect dence of coronary heart disease. JAMA 1984; 251 (3): 351-
of gemfibrozil and clofibrate or the lithogenic index of bile. Scot 364.
Med J 1979; 24: 175. 8. Canner PL: Mortality in coronary drug project during a nine
4. The Inter-Society Commission for Heart Disease Resource Re- year post treatment period (abstr). Am J Cardiol 1983; 51:
port: Primary prevention of atherosclerotic diseases. Circula- 442.

2 November 27, 1987 The American Journal of Medicine Volume 83 (suppl 5B)