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Comparative Effects of Atorvastatin, Simvastatin, and Fenofibrate on Serum Homocysteine Levels in

Patients with Primary Hyperlipidemia
Haralampos J. Milionis, John Papakostas, Anna Kakafika, George Chasiotis, Konstantine Seferiadis and Moses S. Elisaf
J. Clin. Pharmacol. 2003; 43; 825
DOI: 10.1177/0091270003255920

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ARTICLE
MILIONIS ET
10.1177/0091270003255920
LIPID-LOWERING
CLINICAL STUDIES
AL AGENTS AND HOMOCYSTEINE
Comparative Effects of Atorvastatin, Simvastatin,
and Fenofibrate on Serum Homocysteine Levels
in Patients with Primary Hyperlipidemia
Haralampos J. Milionis, MD, John Papakostas, MD,
Anna Kakafika, MD, George Chasiotis, PhD,
Konstantine Seferiadis, PhD, and Moses S. Elisaf, MD, FRSH, FACA
Hyperhomocysteinemia is regarded as an independent risk
factor for cardiovascular disease. Lipid-lowering agents, such
as fibrates, can modify homocysteine levels. However, less is
known about the effect of statin therapy on homocysteine.
The authors compared the effects of atorvastatin (40 mg/
day), simvastatin (40 mg/day), and micronized fenofibrate
(200 mg/day) on the serum concentrations of total
homocysteine, vitamin B12, and folic acid in patients with
primary hyperlipidemia. A total of 128 patients with primary
hyperlipidemia (total cholesterol > 240 mg/dL and triglycer-
ides < 350 mg/dL) were assigned to atorvastatin, simvastatin,
or fenofibrate. Serum lipid and metabolic parameters were
measured at baseline and at 6 and 12 weeks of treatment.
Homocysteine correlated positively with serum creatinine
and uric acid levels and inversely with serum folic acid levels.
All treatment modalities reduced total, low-density lipopro-
tein (LDL) cholesterol, and triglyceride concentrations. High-
density lipoprotein (HDL) cholesterol levels significantly in-
H omocysteine is an intermediate amino acid re-
sulting from the metabolism of methionine and
is known to be toxic to vascular endothelium.1,2
Hyperhomocysteinemia is considered as an independ-
ent risk factor for cardiovascular disease.3,4 Prospective
and retrospective studies have shown that elevated
plasma levels of homocysteine levels are associated
From the Department of Internal Medicine, Medical School, University of
Ioannina, Ioannina, Greece (Dr. Milionis, Dr. Papakostas, Dr. Kakafika, Dr.
Elisaf) and the Laboratory of Biochemistry, University Hospital of Ioannina,
Ioannina, Greece (Dr. Chasiotis, Dr. Seferiadis). Submitted for publication
March 3, 2003; revised version accepted April 28, 2003. Address for re-
prints: Moses Elisaf, MD, FRSH, FACA, Department of Internal Medicine,
Medical School, University of Ioannina, 451 10 Ioannina, Greece.
DOI: 10.1177/0091270003255920
J Clin Pharmacol 2003;43:825-830
CLINICAL STUDIES
creased only in the fenofibrate-treated patients (47.9 ± 12.5
vs. 50.7 ± 12.6 vs. 51.2 12.8 mg/dL, p < 0.01). Atorvastatin
and fenofibrate treatment resulted in a significant reduction
of serum uric acid levels (5.3 ± 1.6 vs. 4.9 ± 1.4 vs. 4.8 ± 1.4 mg/
dL, p < 0.0001 for atorvastatin; 5.6 ± 1.6 vs. 4.3 ± 1.4 vs. 4.4
± 1.4 mg/dL, p < 0.0001 for fenofibrate). Homocysteine levels
were significantly increased only by fenofibrate (10.3 ± 3.3 vs.
14.1 ± 3.8 vs. 14.2 ± 3.6 µU/L, p < 0.001) but did not change
from baseline following statin treatment. Neither statins nor
fenofibrate had any effect on serum vitamin B12 and folic
acid levels. In contrast to fenofibrate, therapeutic dosages of
atorvastatin and simvastatin have a neutral effect on serum
homocysteine levels, which is in favor of their “cardiopro-
tective” properties.
Keywords: Atorvastatin; fenofibrate; folic acid, homocysteine;
lipids; simvastatin; uric acid; vitamin B12
Journal of Clinical Pharmacology, 2003;43:825-830
©2003 the American College of Clinical Pharmacology
with a higher prevalence of occlusive arterial disease,
independent of conventional risk factors.4-8 Total
homocysteine concentrations are mainly determined
by folate and cobalamin status and by renal function.9
Pharmacological agents are also known to modify the
concentration of plasma homocysteine.9-11 Among
them, several different classes of lipid-lowering drugs
(i.e., bile acid resins, niacin, and fish oils) have been
shown to modify homocysteine levels.12 Fibrates have
been shown to increase homocysteine levels, and this
has been partly attributed to the impairment of renal
function.13-20 However, less is known about the effect of
statin therapy on homocysteine levels.21-25
We compared the effects of a synthetic and a natural
statin (i.e., atorvastatin, simvastatin) and a fibrate
(fenofibrate) on serum concentrations of total
825
 MILIONIS ET AL
homocysteine, vitamin B12, and folic acid in patients
with primary hyperlipidemia.
SUBJECTS AND METHODS
Patients attending the Outpatient Lipid Clinic of the
University Hospital of Ioannina, Greece, were recruited
for the study. Men and women with dyslipidemia were
screened for eligibility by medical history, physical ex-
amination, and clinical laboratory evaluation, includ-
ing the lipid profile. No participant had either symp-
tomatic ischemic heart disease or any other vascular
disease. Any lipid-lowering medications had to have
been discontinued for at least 4 weeks. All participants
gave informed consent, and the study protocol was ap-
proved by the institutional ethics committee.
Patients were assigned to the National Cholesterol
Education Program (NCEP) diet for 6 weeks and were
advised to follow this diet throughout the study.26
Fasting serum lipid level entry criteria were total cho-
lesterol > 240 mg/dL at weeks –4 and –2 and/or triglyc-
erides < 350 mg/dL.
Patients with (1) impaired hepatic function
(aminotransferase levels > 2 × normal and history of
chronic liver disease, such as cirrhosis or alcohol
abuse), (2) impaired renal function (serum creatinine
levels > 1.8 mg/dL, and/or a history of chronic renal
disease, such as glomerulonephritis, chronic
pyelonephritis, obstructive renal disease, or
proteinuria), (3) diabetes mellitus (fasting blood glu-
cose > 126 mg/dL), (4) raised thyroid-stimulating hor-
mone (TSH) levels (greater than 5.0 µU/L), and (5) any
medical conditions that might preclude successful
completion were excluded from the study.
Patients taking drugs, such as angiotensin-converting
enzyme inhibitors, angiotensin II receptor antagonists,
or calcium channel blockers on a stabilized dose at
least 8 weeks before entry to the study were considered
eligible. Those receiving drugs possibly affecting the
laboratory parameters tested were excluded.
After a 6-week baseline period, patients were as-
signed to atorvastatin 40 mg, simvastatin 40 mg per
day, or micronized fenofibrate 200 mg in a single noc-
turnal dose for 12 weeks. A food record rating score was
calculated from 3-day diaries kept by the participants
to assess compliance with the diet throughout the
study. Blood samples were taken after a 14-hour over-
night fast for the determination of serum urea,
creatinine, glucose, uric acid, lipids, homocysteine, vi-
tamin B12, and folic acid levels, as well as liver and
muscle enzymes at baseline and at 6 and 12 weeks fol-
lowing treatment initiation.
826 • J Clin Pharmacol 2003;43:825-830
Laboratory
Determinations
The laboratory determinations were carried out by
automated chemical analysis in our laboratory using
an Olympus AU 600 analyzer. The glutamate
dehydrogenase (GLDH) method was used for the deter-
mination of urea levels, the uricase/PAP method (an
enzymatic color test) was used for uric acid, and a mod-
ification of the Jaffé method was used for creatinine.
Glucose was measured by the hexokinase method. The
creatinine clearance was estimated by the following
Cockroft-Gault formula: creatinine clearance = [(140 –
age) × body weight]/(72 × serum creatinine), where lean
body weight is in kg, age is in years, and serum
creatinine is in mg/dL. For women, the result is multi-
plied by a factor of 0.85 to compensate for the lower av-
erage muscle mass.27
The levels of total cholesterol (TC) and triglycerides
(TG) were determined by an enzymatic colorimetric as-
say using a RA-1000 analyzer (Technicon Instruments
Ltd., Terrytown, NY). High-density lipoprotein (HDL)
cholesterol was determined enzymatically from the
supernatant after precipitation of other lipoproteins
with dextran sulfate magnesium. Levels of low-density
lipoprotein (LDL) cholesterol were calculated using the
Friedewald formula.
The AxSYM Homocysteine assay, a fluorescence po-
larization immunoassay (Axis-Shield, Abbott Labora-
tories, Oslo, Norway), was used for the quantitative
measurement of total L-homocysteine in human se-
rum. Serum folate was measured by AxSYM Folate, an
ion capture assay (Abbott Laboratories, Abbott Park,
IL). A chemiluminescent microparticle intrinsic factor
assay was used for the quantitative determination of vi-
tamin B12 in human serum (ARCHITECT B12 assay,
Abbott Laboratories, Abbott Park, IL).
Statistical Analysis
All parameters were expressed as mean values
± standard deviation. Analysis of variance
(ANOVA) for repeated measurements was used to
assess changes in variables after atorvastatin,
simvastatin, and fenofibrate administration. When dif-
ferences were found, Scheffé’s test was used to evaluate
the effects of treatment on the changes from baseline.
Relationships between variables were assessed by
Pearson’s correlation coefficient. Differences were
considered to be significant at p < 0.05. Statistical
analysis was carried out using the program Statistica
(1998, Statsoft, Inc., Tulsa, OK).
 LIPID-LOWERING AGENTS AND HOMOCYSTEINE

RESULTS Creatinine vs. Homocysteine (Casewise MD deletion)

Correlation: r = ,55053 ; p<0.00001

A total of 128 patients were included in the study.

Atorvastatin was prescribed in 64 patients (36 men and
28 women, ages 58.5 ± 8.3 years old), simvastatin was

Homocysteine (microu/L)
given to 42 patients (24 men and 18 women, ages 59.6
± 9.8 years old), and 22 patients (13 men and 9 women,
ages 58.1 ± 8.6 years old) were assigned to fenofibrate.
At baseline, serum total homocysteine levels corre-
lated positively with serum creatinine (r = 0.5505, p <
0.0001) and uric acid (r = 0.3233, p = 0.003) and in-
versely with serum folic acid levels (r = –0.3622, p =
0.001) in the whole study population (Figure 1).
Creatinine (mg/dL)
All therapeutic modalities (atorvastatin,
simvastatin, or fenofibrate) resulted in a significant re- Uric acid vs. Homocysteine (Casewise MD deletion)
duction in total cholesterol (TC), low-density lipopro- Correlation: r = ,32326 ; p=0.002

tein (LDL) cholesterol, and triglyceride (TG) concentra-

tions. High-density lipoprotein (HDL) cholesterol
levels were increased by fenofibrate, but they did not
Homocysteine (microu/L)
change significantly from baseline following statin
therapy (Table I).
Uric acid levels were significantly lowered in the
atorvastatin and fenofibrate groups but not in the
simvastatin-treated group (Table I).
Statin treatment produced no significant changes in
serum creatinine levels or in calculated creatinine
clearance measurements. In contrast, fenofibrate treat-
ment resulted in a significant increase of serum Uric acid (mg/dL)

creatinine and a corresponding reduction in creatinine

clearance measurements (Table I). Folic acid vs. Homocysteine (Casewise MD deletion)
Correlation: r = -,3622 ; p=0.001
Homocysteine levels were not modified in patients
receiving either atorvastatin or simvastatin but were
significantly raised by fenofibrate (Table I). Folic acid
and vitamin B12 levels did not significantly change
Homocysteine (microu/L)

from baseline values in all treatment groups.

Finally, no correlation was found between
“posttreatment minus baseline” changes in serum total
homocysteine levels and serum lipid levels, uric acid
levels, serum creatinine, or creatinine clearance
estimates.

DISCUSSION Folic acid (ng/mL)

Elevated homocysteine levels are considered as a
rather common, independent, and possibly causal risk
factor for cardiovascular disease.1-4 Increasing age,
male gender, habits (such as tobacco addiction, exces-
sive alcohol drinking, and sedentary lifestyle) are asso-
ciated with hyperhomocysteinemia.9 Renal function
impairment and other disease states such as
hypothyroidism or neoplasias are also associated with
increased serum homocysteine concentrations.9 More-
Figure 1. Correlations between serum total homocysteine and se-
rum creatinine, uric acid, and folic acid levels at pretreatment.
over, several medications may interfere with
homocysteine levels.10-12
This study was designed to compare the effects of
statin and fibrate treatment on homocysteine levels in

CLINICAL STUDIES 827

 MILIONIS ET AL

Table I Serum Parameters in Patients Treated with Atorvastatin,

Simvastatin, and Fenofibrate at Pretreatment and after 6 and 12 Weeks of Treatment
Posttreatment
Variable Baseline 6 Weeks 12 Weeks p-Value

Atorvastatin (n = 64)
TC (mg/dL) 303.0 ± 57.8 187.6 ± 45.2 189.9 ± 45.7 < 0.0001
LDL-C (mg/dL) 223.3 ± 54.0 120.3 ± 40.3 116.4 ± 35.3 < 0.0001
TG (mg/dL) 167.7 ± 78.2 120.3 ± 40.3 113.4 ± 53.1 < 0.0001
HDL-C (mg/dL) 47.2 ± 12.1 44.6 ± 10.7 49.6 ± 2.3 NS
Creatinine (mg/dL) 0.9 ± 0.1 0.9 ± 0.1 0.9 ± 0.1 NS
CLcr (mL/min) 85.3 ± 19.4 84.8 ± 19.9 85.0 ± 19.7 NS
Homocysteine (µu/L) 10.5 ± 3.6 10.2 ± 3.4 10.8 ± 3.8 NS
Vitamin B12 (pg/mL) 324.3 ± 91.0 327.8 ± 117.3 328.3 ± 98.2 NS
Folate (ng/mL) 9.2 ± 2.6 9.7 ± 2.7 9.2 ± 2.5 NS
Uric acid (mg/dL) 5.3 ± 1.6 4.9 ± 1.4 4.8 ± 1.4 < 0.0001
Simvastatin (n = 42)
TC (mg/dL) 269.6 ± 40.6 197.5 ± 28.9 196.9 ± 37.0 < 0.0001
LDL-C (mg/dL) 166.7 ± 61.7 100.8 ± 53.0 80.2 ± 62.5 < 0.0001
TG (mg/dL) 155.1 ± 82.6 125.5 ± 55.1 130.3 ± 57.2 < 0.001
HDL-C (mg/dL) 51.3 ± 12.9 49.8 ± 9.6 51.7 ± 12.6 NS
Creatinine (mg/dL) 1.0 ± 0.2 1.0 ± 0.2 1.0 ± 0.2 NS
CLcr (mL/min) 78.9 ± 21.4 78.0 ± 22.2 77.9 ± 21.6 NS
Homocysteine (µu/L) 10.8 ± 3.4 10.3 ± 2.6 10.9 ± 3.1 NS
Vitamin B12 (pg/mL) 332.7 ± 113.6 341.6 ± 122.0 336.1 ± 106.5 NS
Folate (ng/mL) 9.4 ± 2.8 9.6 ± 3.1 9.6 ± 2.9 NS
Uric acid (mg/dL) 5.3 ± 1.4 5.2 ± 1.4 5.3 ± 1.5 NS
Fenofibrate (n = 22)
TC (mg/dL) 264.3 ± 43.5 225.0 ± 36.4 227.4 ± 24.7 < 0.0001
LDL-C (mg/dL) 196.2 ± 51.3 157.8 ± 39.6 154.6 ± 42.7 < 0.0001
TG (mg/dL) 251.7 ± 65.5 181.7 ± 59.3 163.1 ± 42.0 < 0.0001
HDL-C (mg/dL) 47.9 ± 12.5 50.7 ± 12.6 51.2 ± 12.8 < 0.01
Creatinine (mg/dL) 0.9 ± 0.12 1.03 ± 0.14 1.04 ± 0.12 < 0.0001
CLcr (mL/min) 84.8 ± 23.5 71.4 ± 18.3 73.1 ± 16.9 < 0.01
Homocysteine (µu/L) 10.3 ± 3.3 14.1 ± 3.8 14.2 ± 3.6 < 0.001
Vitamin B12 (pg/mL) 332.7 ± 113.6 341.6 ± 122.0 336.1 ± 106.5 NS
Folate (ng/mL) 9.1 ± 2.5 9.3 ± 2.9 9.2 ± 2.6 NS
Uric acid (mg/dL) 5.6 ± 1.6 4.3 ± 1.4 4.4 ± 1.4 < 0.0001
TC, total cholesterol; LDL-C: low-density lipoprotein cholesterol; TG, triglycerides; HDL-C, high-density cholesterol; CLcr, creatinine clearance; NS,
nonsignificant.

patients with primary hyperlipidemia. A natural statin
(simvastatin) and a synthetic statin (atorvastatin) were
used. All treatment modalities proved efficient in im-
proving the lipid profile (reducing TC, LDL cholesterol,
and TG levels). However, differences were docu-
mented with regard to nonlipid biochemical risk fac-
tors, including serum uric acid and homocysteine.
Atorvastatin and fenofibrate, but not simvastatin, led to
a significant reduction of uric acid levels. An inde-
pendent association between elevated uric acid serum
levels and increased atherosclerotic disease or mortal-
ity is evident in some epidemiological studies.28-31
However, the pathophysiological mechanisms under-
lying the association of serum uric acid with
cardiovascular disease and all-cause mortality are not
fully clarified.32 There is evidence that among fibrates,
only fenofibrate can significantly affect uric acid me-
tabolism.33,34 A number of studies have showed that
fenofibrate can significantly decrease serum uric acid
levels by augmenting renal urate excretion, and this ef-
fect is independent of any change in serum lipid pa-
rameters.35 Moreover, our findings confirmed the
hypouricemic effect of atorvastatin that has been de-
scribed previously.23,36,37 Simvastatin treatment seems

828 • J Clin Pharmacol 2003;43:825-830

 LIPID-LOWERING AGENTS AND HOMOCYSTEINE
not to interfere with uric acid metabolism. However,
the clinical relevance of uric acid reduction following
lipid-modifying treatment needs to be determined.
In contrast to fenofibrate, statin therapy had a neu-
tral effect on homocysteine. These findings are in
agreement with the small number of studies evaluat-
ing the influence of statin therapy on homocysteine
levels.21-25 However, it has been reported that higher
doses of simvastatin (i.e., 80 mg daily) produce a sig-
nificant reduction in total serum homocysteine lev-
els.21 Interestingly, in a pilot study run for the Study
Evaluating Additional Reduction in Cholesterol and
Homocysteine (SEARCH) trial, simvastatin (80 mg
daily) combined with vitamin B12 and folic acid pro-
duced a similar reduction in homocysteine levels to vi-
tamin supplementation alone.22 On the other hand,
treatment with fenofibrate was associated with a signif-
icant increase of serum homocysteine. It is of import
that a simultaneous increase of creatinine levels and a
corresponding reduction in creatinine clearance mea-
surements was also noted. A number of studies have
shown that fibrates can significantly increase serum
homocysteine in both the fasting and fed state.13-20 Folic
acid supplementation ameliorates this “side effect” of
fenofibrate treatment.20 The underlying mechanisms
are not clear yet. Changes in renal function induced by
fibrates have been implicated for the increase in
homocysteine levels following fibrate treatment.38-40
This may be due to the activation of peroxisome
proliferator-activated receptors (PPARs), which
downregulates the renal COX-2 enzyme system,
thereby decreasing the synthesis of vasodilating
prostaglandins and consequently the glomerular filtra-
tion rate.18,40 It has been postulated that elevated
homocysteine levels in the setting of renal dysfunction
(increased serum creatinine) are not due to impaired
urinary excretion but rather due to impaired metabo-
lism of homocysteine by the kidney.40 However, some
authorities suggest that the increase of creatinine levels
could also reflect an increase in the metabolic turnover
in muscles caused by PPAR-alpha activation.25,40 Inter-
estingly, it has been recently shown that fenofibrate
increases serum total homocysteine in rodents in a
PPAR-alpha manner.41 However, this increase in rats
was limited to protein-bound homocysteine (and not
the free-reduced fraction), which is considered less
atherogenic.41 Therefore, further studies are needed to
determine the clinical relevance of hyperhomo-
cysteinemia due to fibrates.
In conclusion, this study clearly demonstrates that
patients with primary hyperlipidemia can be effi-
ciently treated with either statins or fibrates. However,
lipid-lowering agents exert different actions on
CLINICAL STUDIES
nonlipid biochemical risk factors, such as uric acid and
homocysteine. The neutral effect of therapeutic dosages
of either atorvastatin or simvastatin on homocysteine
levels is in favor of their “cardioprotective” properties
and might contribute to the reduction of cardiovascular
events.
REFERENCES
1. Wesch GN, Loscalzo J: Homocysteine and atherosclerosis. N Engl J
Med 1998;338:1042-1050.
2. Mangoni AA, Jackson SHD: Homocysteine and cardiovascular
disease: current evidence and future prospects. Am J Med
2002;112:556-565.
3. Nygard O, Vollset SE, Refsum H, Brattstrom L, Ueland PM: Total
homocysteine and cardiovascular disease. J Intern Med 1999;246:
425-454.
4. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B,
et al: Hyperhomocysteinemia: an independent risk factor for vascular
disease. N Engl J Med 1991;324:1149-1155.
5. Boushey CJ, Beresfors SAA, Omenn GS, Motulsky AG: A quantita-
tive assessment of plasma homocysteine as a risk factor of vascular
disease: probable benefits of increasing folic acid intakes. JAMA
1995;274:1049-1057.
6. Graham IM, Daly LE, Refsum H, Robinson K, Brattstrom LE,
Ueland PM, et al: Plasma homocysteine as a risk factor for vascular
disease. The European Concerted Action Project. JAMA 1997;277:
1775-1781.
7. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M,
Vollset SE: Plasma homocysteine levels and mortality in patients
with coronary artery disease. N Engl J Med 1997;337:230-236.
8. Nurk E, Tell GS, Vollset SE, Nygard O, Refsum H, Ueland PM:
Plasma total homocysteine and hospitalizations for cardiovascular
disease: the Hordaland Homocysteine Study. Arch Intern Med
2002;162:1374-1381.
9. Medina MA, Amores-Sanchez MI: Homocysteine: an emergent
cardiovascular risk factor. Eur J Clin Invest 2000;30:754-762.
10. van Guldener C, Stehouwer CD: Homocysteine-lowering treat-
ment: an overview. Expert Opin Pharmacotherap 2001;2:1449-1460.
11. Nallamothu BK, Fendrick AM, Omenn GS: Homocyst(e)ine and
coronary heart disease: pharmacoeconomic support for interven-
tions to lower hyperhomocyst(e)inemia. Pharmacoeconomics
2002;20:429-442.
12. Desouza C, Keebler M, McNamara DB, Fonseca V: Drugs affecting
homocysteine metabolism: impact on cardiovascular risk. Drugs
2002;62:605-616.
13. Dierkes J, Westphal S, Luley C: Serum homocysteine after therapy
with fenofibrate bezafibrate. Lancet 1999;354:219-220.
14. Chan N, Chan JCN: Implication of fibrate therapy for
homocysteine. Lancet 1999;354:1208-1209.
15. Jonkers IJAM, de Man FHAF, Onkenhout W, van der Laarse A,
Smelt AHM: Implication of fibrate therapy for homocysteine. Lancet
1999;354:1208.
16. Goffin E, Jamar F, Desager J-P, Devuyst O: Implication of fibrate
therapy for homocysteine. Lancet 1999;354:1209.
17. de Lorgeril M, Salen P, Paillard F, Lacan P, Richard G: Lipid-
lowering drugs and homocysteine. Lancet 1999;353:209-210.
829
 MILIONIS ET AL
18. Westphal S, Dierkes J, Luley C: Effects of fenofibrate and
gemfibrozil on plasma homocysteine. Lancet 2001;358:39-40.
19. Bissonette R, Treacy, Rozen R, Boucher B, Cohn JS, Genest J Jr:
Fenofibrate raises plasma homocysteine levels in the fasted and fed
states. Atherosclerosis 2001;155:455-462.
20. Stulc T, Melenovsky V, Grauova B, Kozich V, Ceska R: Folate
supplementation prevents plasma homocysteine increase after
fenofibrate therapy. Nutrition 2001;17:721-723.
21. Luftjohann D, Sigit JI, Locatelli S, von Bergmann K: High-dose
simvastatin (80 mg:day) decreases plasma concentrations of total
homocyst(e)ine in patients with hypercholesterolemia. Atheroscle-
rosis 2001;155:265-266.
22. MacMahon M, Kirkpatrick C, Cummings CE, Clayton A, Robinson
PJ, Tomiak RH, et al: A pilot study with simvastatin and folic acid/
vitamin B12 in preparation for the Study of the Effectiveness of Addi-
tional Reductions in Cholesterol and Homocysteine (SEARCH). Nutr
Metab Cardiovasc Dis 2000;10:195-203.
23. Giral P, Bruckert E, Jacob N, Chapman MJ, Foglietti M-J, Turpin G:
Homocysteine and lipid lowering agents: a comparison between
atorvastatin and fenofibrate in patients with mixed hyperlipidemia.
Atherosclerosis 2001;154:421-427.
24. Malik J, Melenovsky V, Wichterle D, Haas T, Simek J, Ceska R,
et al: Both fenofibrate and atorvastatin improve vascular reactivity in
combined hyperlipidaemia (fenofibrate versus atorvastatin trial—
FAT). Cardiovasc Res 2001;52:290-298.
25. Melenovsky V, Malik J, Wichterle D, Simek J, Pisarikova A, Skrha
J, et al: Comparison of the effects of atorvastatin or fenofibrate on
nonlipid biochemical risk factors and the LDL particle size in sub-
jects with combined hyperlipidemia. Am Heart J 2002;144:e6.
26. Executive summary of the third report of the National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults (Adult Treatment
Panel III). JAMA 2001;285:2486-2497.
27. Cockroft DW, Gault MH: Prediction of creatinine clearance form
serum creatinine. Nephron 1976;16:31-39.
28. Bengtsson C, Lapidus L, Stendahl C, Waldenstrom J:
Hyperuricemia and risk of cardiovascular disease and overall death:
a 12-year follow up of participants in the population study of women
in Gothenburg, Sweden. Acta Med Scand 1988;224:549-555.
29. Brand FN, McGee DL, Kannel WB, Stokes J, Castelli WP:
Hyperuricemia as a risk factor of coronary heart disease: the
Framingham Study. Am J Epidemiol 1985;121:11-18.
830 • J Clin Pharmacol 2003;43:825-830
30. Freedman DS, Williamson DF, Gunter EW, Byers T: Relation of se-
rum uric acid to mortality and ischemic heart disease: the NHANES I
Epidemiologic Follow-Up Study. Am J Epidemiol 1995;141:637-644.
31. Liese AD, Hense HW, Lowel H, Doring A, Tietze M, Keil U: Asso-
ciation of serum uric acid with all-cause and cardiovascular disease
mortality and incident myocardial infarction in the MONICA
Augsburg cohort: World Health Organization monitoring trends and
determinants in cardiovascular diseases. Epidemiology 1999;10:391-
397.
32. Nieto FJ, Iribaren C, Gross MD, Comstock GW, Cutler RG: Uric
acid and serum antioxidant capacity: a reaction to atherosclerosis?
Atherosclerosis 2000;148:131-139.
33. Elisaf M, Tsimichodimos V, Bairaktari E, Siamopoulos KC: Effect
of micronized fenofibrate and losartan combination on uric acid me-
tabolism in hypertensive patients with hyperuricemia. J Cardiovasc
Pharmacol 1999;34:60-63.
34. Liamis G, Bairaktari ET, Elisaf MS: Effect of fenofibrate on serum
uric acid levels. Am J Kidney Dis 1999;34:594.
35. Milionis HJ, Elisaf MS: Management of hypertension and
dyslipidaemia in patients presenting with hyperuricaemia: case his-
tories. Curr Med Res Opin 2000;16:164-170.
36. Marais AD, Firth JC, Bateman ME, Byrnes P, Martens C, Mountey
J: Atorvastatin: an effective lipid modifying agent in familial hyper-
cholesterolemia. Arterioscler Thromb Vasc Biol 1997;17:1527-1531.
37. Kakafika A, Tsimichodimos V, Elisaf M: Effect of atorvastatin on
serum uric acid levels. Atherosclerosis 2001;158:255.
38. Lipscombe J, Lewis GF, Cattran D, Bargman JM: Deterioration in
renal function associated with fibrate therapy. Clin Nephrol
2001;55:39-44.
39. Tsimichodimos V, Kakafika A, Elisaf M: Fibrate treatment can in-
crease serum creatinine levels. Nephrol Dial Transplant 2001;
16:1301.
40. Elisaf M: Effects of fibrates on serum metabolic parameters. Curr
Med Res Opin 2002;18:269-276.
41. Legendre C, Causse E, Chaput E, Salvayre R, Pineau T, Edgar AD:
Fenofibrate induces a selective increase of protein-bound
homocysteine in rodents: a PPARalpha-mediated effect. Biochem
Biophys Res Commun 2002;295:1052-1056.