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Fenofibrate-associated nephrotoxicity: A review of current evidence

Article  in  American journal of health-system pharmacy: AJHP: official journal of the American Society of Health-System Pharmacists · July 2013
DOI: 10.2146/ajhp120131 · Source: PubMed

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 clinical Consultation  Fenofibrate

c l i n i c a l   c o n s u ltat i o n

Fenofibrate-associated nephrotoxicity: A review

of current evidence
Rebecca L. Attridge, Christopher R. Frei, Laurajo Ryan, Jim Koeller, and William D. Linn

T
he World Health Organization
has defined an adverse drug re-
action as a “response to a drug
which is noxious and unintended
and which occurs at doses normally
used in man for prophylaxis, diag-
nosis, or therapy of a disease.”1 Many
adverse reactions are not recognized
at the time of drug approval. Studies
of investigational drugs generally in-
clude limited populations with spe-
cific inclusion and exclusion criteria.
Prescribers, however, utilize drugs in
much larger and more heterogeneous
populations, emphasizing the impor-
tance of postmarketing surveillance.
Fenofibrate is used in the treat-
ment of dyslipidemia.2,3 In the past
decade, reports of fenofibrate-
associated nephrotoxicity have
surfaced. 3-5 This adverse reaction
was not fully elucidated in the pre-
scribing information when the drug
was first approved. 6-8 Since drug
approval, case reports as well as ret-
rospective and prospective studies
have reported fenofibrate-associated
nephrotoxicity. However, the ad-
verse effect is underrecognized in
the clinical setting.9
Purpose. The literature describing
fenofibrate-associated nephrotoxicity was
reviewed.
Summary. Fenofibrate-associated neph-
rotoxicity is an underrecognized adverse
effect that is being reported with increas-
ing frequency in the medical literature. A
MEDLINE search identified articles describ-
ing fenofibrate-associated nephrotoxicity.
Two retrospective chart reviews reported
this adverse reaction in transplant recipients
and patients with renal insufficiency. A case
series of six patients noted that the adverse
reaction also occurred in patients without a
predisposition to renal injury. Two small pro-
spective studies have examined fenofibrate-
associated nephrotoxicity, with conflicting
findings regarding the mechanism. Finally, a
large retrospective review and a population-
based cohort study found that patients
with preexisting renal disease or taking
high-dosage fenofibrate have a higher risk
of developing fenofibrate-associated neph-
rotoxicity. Fenofibrate-associated nephro-
toxicity was shown to be reversible with
Clinical use of fenofibrate
Fenofibrate, a fibric acid deriva-
tive, was approved by the Food and
Drug Administration (FDA) in 1998
both discontinuation and continued use of
fenofibrate, though one study found that
the elevations in serum creatinine (SCr) lev-
els were permanent in study participants.
Some argue that SCr elevations described
in these articles were not due to renal
toxicity but may be attributed to reversible
mechanisms. While several mechanisms
may be biologically plausible, none of the
theories have been tested in clinical trials.
A possible mechanism for the increase in
SCr levels may include changes in renal
hemodynamics causing volume depletion
and the impairment of generation of va-
sodilatory prostaglandins, leading to renal
vasoconstriction.
Conclusion. Fenofibrate-associated neph-
rotoxicity is an underrecognized adverse
drug reaction. Several published reports
have detailed possible etiologies; how-
ever, data detailing the true incidence of
fenofibrate-associated nephrotoxicity and
its associated risk factors are limited.
Am J Health-Syst Pharm. 2013; 70:1219-
25
for the treatment of hypertriglyc-
eridemia and atherogenic dyslipid-
emia.3-5,8 Fenofibrate is a synthetic
ligand that activates peroxisome

Rebecca L. Attridge, Pharm.D., M.Sc., is Assistant Professor,
Feik School of Pharmacy, University of the Incarnate Word, San
Antonio, TX, and Adjunct Assistant Professor, University of Texas
Health Science Center (UTHSC), San Antonio. Christopher R. Frei,
Pharm.D., M.Sc., is Associate Professor; Laurajo Ryan, Pharm.D.,
M.Sc., is Clinical Associate Professor; and Jim Koeller, M.Sc., is
Professor, College of Pharmacy, University of Texas, San Antonio, and
UTHSC. William D. Linn, Pharm.D., is Assistant Dean, Department
Chair, and Associate Professor of Pharmacy Practice, Feik School of
Pharmacy, University of the Incarnate Word.
Address correspondence to Dr. Attridge at the Feik School of Phar-
macy, University of the Incarnate Word, 4301 Broadway, CPO 99, San
Antonio, TX 78209 (rowens@uiwtx.edu).
Kyllie Ryan-Hummel is acknowledged for her assistance with
manuscript formatting.
The authors have declared no potential conflicts of interest.
Copyright © 2013, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/13/0702-1219$06.00.
DOI 10.2146/ajhp120131

Am J Health-Syst Pharm—Vol 70 Jul 15, 2013 1219

 clinical consultation  Fenofibrate
The Clinical Consultation section features
articles that provide brief advice on how to
handle specific drug therapy problems. All
articles are based on a systematic review
of the literature. The assistance of ASHP’s
Section of Clinical Specialists and Scientists
in soliciting Clinical Consultation submis-
sions is acknowledged. Unsolicited submis-
sions are also welcome.
proliferator-activated receptor a
(PPARa), leading to changes in lipid
metabolism, glucose homeostasis,
and insulin resistance.3-5,10-12 Feno-
fibrate decreases triglyceride levels
by 20–50%, increases high-density-
lipoprotein levels by 10–25%, and
decreases low-density-lipoprotein
levels by 5–20%3,4,13,14
The effect of fenofibrate on car-
diovascular outcomes has been as-
sessed in three trials. In the Diabetes
Atherosclerosis Intervention Study,
418 patients with diabetes with or
without a history of coronary artery
disease were randomized to receive
fenofibrate or placebo for at least 3
years.15 The study found that patients
treated with fenofibrate had signifi-
cant improvements in the surrogate
outcomes of minimum luminal
narrowing (p = 0.029) and progres-
sion of diameter stenosis (p = 0.02);
however, no significant difference
in cardiovascular events was found
between groups. The Fenofibrate
Intervention and Event Lowering in
Diabetes (FIELD) study evaluated
9795 patients with diabetes with or
without a history of coronary heart
disease (CHD) treated with feno-
fibrate or placebo.16 After 5 years,
the fenofibrate-treated group had a
significant reduction in nonfatal
myocardial infarction (p = 0.01);
however, this was coupled with a
nonsignificant increase in CHD
mortality. The Action to Control
Cardiovascular Risk in Diabetes
(ACCORD) trial randomized 5518
patients with type 2 diabetes treated
with simvastatin to receive fenofi-
brate or placebo for a mean dura-
1220 Am J Health-Syst Pharm—Vol 70 Jul 15, 2013
tion of 4.7 years.17 The annual rate
of the composite outcome of first
occurrence of nonfatal myocardial
infarction, nonfatal stroke, or death
from cardiovascular causes did not
significantly differ between groups.
Fenofibrate is generally well tol-
erated by most patients3-5; however,
fenofibrate may cause rare but seri-
ous adverse effects, including choleli-
thiasis and pancreatitis.3,4,6-8,18 Neph-
rotoxicity, another serious adverse
reaction associated with fenofibrate
therapy, has been reported with in-
creasing frequency.3,12,19
Literature review
A MEDLINE search (1950 to May
2012) was conducted using the key-
words fenofibrate and nephrotoxic-
ity and MEDLINE Subject Heading
terms procetofen; kidney diseases; kid-
ney failure, acute; and kidney. Animal
studies and studies that focused on
rhabdomyolysis were excluded from
this review. Additional studies were
found by reviewing the references
of trials identified in the MEDLINE
search.
Retrospective analyses. In 2000,
Broeders and colleagues19 retrospec-
tively evaluated increases in serum
creatinine (SCr) and blood urea
nitrogen (BUN) levels in 27 patients
treated with a fibrate (n = 8 patients
with baseline renal insufficiency;
n = 19 transplant recipients [15 renal,
4 heart or heart–lung transplants]).
Nephrotoxicity was defined as an
increase in SCr concentration of at
least 0.2 mg/dL temporally related to
fenofibrate initiation. Patients were
excluded if they had other plausible
etiologies for nephrotoxicity. Fenofi-
brate 100–200 mg daily was used by
25 patients; bezafibrate and ciprofi-
brate were used in 1 patient each. The
transplant recipients were concur-
rently receiving immunosuppressive
medications, including cyclosporine.
Patients’ baseline SCr concentra-
tion ranged from 0.9 to 2.9 mg/dL.
Forty percent of patients experienced
an increase in SCr concentration,
and 36% had a concomitant increase
in BUN concentration. The mean
time from fibrate initiation to renal
dysfunction was 1.9 months (range,
7 days–5 months). SCr concentration
returned to baseline levels in 18 of
24 patients after fibrate discontinu-
ation. The time to return to baseline
SCr value ranged from 15 days to 1
month, with 2 patients requiring up
to 3 months for reversal. Six trans-
plant recipients had a permanent
increase in SCr level. In addition, 1
patient developed acute renal failure
requiring hemodialysis. No correla-
tion was observed between baseline
SCr concentration and the percent
increase in SCr level (r = 0.29, p =
0.14) or between the fenofibrate
dosage and the percent increase in
SCr concentration. There were no
significant differences in serum cy-
closporine levels before or during
fenofibrate therapy.
In 2001, Lipscombe and col-
leagues20 conducted a retrospective
review of 10 men who had a history
of renal insufficiency and received fi-
brate therapy; the 10 patients received
a total of 17 treatment cources (13
with fenofibrate, 3 with gemfibrozil,
and 1 with bezafibrate). Six patients
had received renal transplants, 5 of
whom were taking cyclosporine. The
patients’ mean ± S.D. pretreatment
SCr concentration was 2.1 ± 0.2
mg/dL (range, 1.4–3 mg/dL), and
the mean ± S.D. peak SCr concentra-
tion during fibrate therapy was 2.8
± 0.2 mg/dL (p < 0.001 versus base-
line), a 35% increase from baseline.
After fibrate discontinuation, the
mean ± S.D. SCr concentration was
2.1 ± 0.1 mg/dL (p < 0.001 versus
peak SCr concentration). The mean
time to peak SCr was 78 days (range,
7–312 days), and the mean time to
return to baseline SCr concentra-
tion was 89 days (range, 8–257 days).
Both of these time frames were likely
overestimated due to limitations in
the time to clinic follow-up. BUN
concentration also increased with
therapy and decreased after drug

discontinuation. Serum cyclosporine
levels did not change during fibrate
treatment.
The results of both of these stud-
ies suggest that increases in SCr levels
are possible with fibrate therapy if
patients have preexisting renal in-
jury.19,20 However, Lipscombe et al.20
reported this effect to be reversible
in most patients, while Broeders and
colleagues19 found that increases in
SCr values during fibrate therapy
may be permanent.
Ritter and Nabulsi 21 reported
a case series of six patients whose
SCr levels increased after the initia-
tion of fenofibrate 67–201 mg daily.
Baseline SCr concentrations ranged
from 0.8 to 1.6 mg/dL. The peak
SCr concentration during treatment
ranged from 1.4 to 2.2 mg/dL and
fell to 0.8–1.5 mg/dL after drug dis-
continuation. The time to elevation
in SCr levels ranged from two to four
months, and the time to resolution
ranged from one to seven months.
One patient experienced an increase
in SCr concentration that did not
resolve with drug discontinuation.
The authors recommended obtain-
ing a baseline SCr concentration
and performing routine monitoring
every one to two months in patients
receiving fenofibrate.
Paul and Mohan 22 examined
fenofibrate-associated nephrotoxic-
ity in two retrospective reviews. The
first review was a three-year follow-
up of 50 patients with diabetes who
received fenofibrate but had no prior
renal insufficiency. Twenty percent
had an increase in SCr concentration
of 0.2–0.4 mg/dL during fenofibrate
therapy. The second review included
50 patients with diabetes who had
nephropathy and were treated with
fenofibrate, 56% of whom experi-
enced an increase in SCr concentra-
tion during therapy. The degree of
SCr concentration increase was not
reported for the second review. The
investigators concluded that feno-
fibrate had no significant effect in
patients with normal renal function
clinical Consultation  Fenofibrate
but should not be used in patients
with renal disease. This recommen-
dation is in agreement with previous
reports that patients with preexisting
renal disease have a higher likelihood
of developing fenofibrate-associated
nephrotoxicity.
In 2004, Angeles and colleagues9
published a case series of three renal
transplant recipients who developed
fenofibrate-associated nephrotox-
icity. Patients received fenofibrate
54–67 mg daily for hyperlipidemia
secondar y to immunosuppres-
sive medications. The baseline SCr
concentration ranged from 1 to
2 mg/dL, and the peak SCr con-
centration during therapy ranged
from 3.1 to 3.9 mg/dL. The time
from therapy initiation to elevated
SCr levels ranged from three to five
months. Fenofibrate was discontin-
ued in all three patients; thereafter,
SCr concentrations decreased to
1.2–2 mg/dL within one to three
months. Serum cyclosporine levels
remained within the desired range
during fenofibrate therapy. Renal
biopsies were performed on all three
patients during peak SCr concentra-
tions and revealed evidence of proxi-
mal tubular injury consistent with
drug toxicity. The histology was not
consistent with calcineurin inhibitor
nephrotoxicity or allograft rejection.
The authors urged clinicians to be
cautious with prescribing fenofibrate
in renal transplant recipients.
McQuade et al.23 published a case
report describing a 60-year-old His-
panic man on fenofibrate therapy
with stage IV chronic kidney disease.
Two weeks after the initiation of
fenofibrate 48 mg daily, the patient’s
SCr and BUN concentrations in-
creased from 3 and 25 mg/dL to 3.5
and 30 mg/dL, respectively, with a
corresponding decrease in glomeru-
lar filtration rate (GFR) from 24.8
to 17.9 mL/min/1.73 m2. After four
weeks of therapy, his SCr concentra-
tion increased to 3.7 mg/dL, a 23%
increase from baseline. The dosage
was increased from 48 to 145 mg
Am J Health-Syst Pharm—Vol 70 Jul 15, 2013
daily due to persistently elevated
triglyceride levels, and the patient’s
SCr concentration increased further
to 4.7 mg/dL. Fenofibrate was dis-
continued; four days later, his SCr
concentration decreased to 3.3
mg/dL without hemodialysis. The
patient’s SCr concentration con-
tinued to decline over the next six
weeks, returning to 3.2 mg/dL, with
a GFR of 20.5 mL/min/1.73 m2. Two
24-hour urine creatinine collections
were performed during fenofibrate
therapy, and neither showed a par-
allel increase in urinary creatinine
excretion. After assessing the adverse
event and its possible relationship to
fenofibrate, the authors concluded
that there was a possible association
between the drug and the patient’s
increased SCr levels.
A recent retrospective review of
428 patients found that 115 patients
(27%) had an increase in SCr con-
centration of ≥0.3 mg/dL within six
months of initiating fenofibrate.24
In a multivariable regression model,
preexisting renal disease and ini-
tiation of high-dose fenofibrate were
found to be independent predictors
for the development of fenofibrate-
associated nephrotoxicity.
Prospective studies. Hottelart and
colleagues25,26 enrolled patients with
normal renal function or moderate
chronic renal insufficiency and hy-
perlipidemia in a prospective study
evaluating fenofibrate-associated
nephrotoxicity. The trial was per-
formed in two phases, each with 13
patients. The mean ± S.E. estimated
GFR was 67 ± 8 mL/min.
In the first phase of the study,
patients were discontinued from
current fenofibrate therapy for a
two-week washout period. A 24-hour
urine collection was performed, and
fasting SCr, BUN, electrolyte, and
lipid panels were measured. Renal
blood flow and GFR were measured
by aminohippurate sodium and
inulin clearance, respectively. Feno-
fibrate 200 mg daily or every other
day was initiated if the estimated
1221
 clinical consultation  Fenofibrate
GFR was less than 40 mL/min. All
laboratory tests were repeated after
two weeks. The second phase of the
study followed the same design; the
SCr value was determined using the
Jaffe reaction and high-performance
liquid chromatography (HPLC).
The first phase of the study found
that after two weeks of fenofibrate
therapy, there was an increase in
SCr concentration from baseline
(increased from 1.66 to 1.92 mg/dL,
p = 0.014) but no change in amino-
hippurate sodium, inulin, and urine
creatinine concentrations. In the
second phase of the study, patients
treated with fenofibrate had signifi-
cantly higher SCr (1.7 mg/dL versus
1.5 mg/dL, p < 0.0001), BUN (27.5
mg/dL versus 24.9 mg/dL, p < 0.002),
and urine creatinine (1457 mg per 24
hours versus 1334 mg per 24 hours,
p < 0.01) concentrations; creatinine
clearance (CLcr) was unchanged. A
correlation was shown between the
Jaffe reaction and HPLC, indicating
that the increase in SCr concentra-
tion was not due to assay interference
(r2 = 0.675, p = 0.0006). These find-
ings suggest that even though fenofi-
brate is associated with increased SCr
levels, glomerular function may not
be affected.
The FIELD trial was a multi-
national, randomized, controlled
trial in patients with type 2 diabetes
evaluating the effects of fenofibrate
therapy on cardiovascular events
over a median follow-up of five
years.16 Patients with renal impair-
ment (SCr concentration of >1.5
mg/dL) were excluded. Patients who
were randomized to fenofibrate had
a mean increase in SCr concentration
of 0.1 mg/dL (1.0 mg/dL versus 0.9
mg/dL with placebo, p < 0.001). In
661 patients who were reevaluated
after discontinuation of the study
drug, SCr concentrations decreased
from 1.1 to 0.9 mg/dL in those in the
fenofibrate group, while those receiv-
ing placebo had no change in SCr
value. In addition, 73 patients (2%)
taking fenofibrate versus 48 patients
1222 Am J Health-Syst Pharm—Vol 70 Jul 15, 2013
(1%) receiving placebo experienced
SCr concentration increases of >2.3
mg/dL. The authors did not believe
this increase in SCr concentration
was clinically significant and noted
that the elevation fully reversed six
to eight weeks after fenofibrate dis-
continuation. In the FIELD Helsinki
renal substudy, 170 patients from the
Finland study site were evaluated.27
The results of the substudy revealed
that the increase in SCr levels dur-
ing fenofibrate therapy was not ac-
companied by an increase in urinary
creatinine but did translate to signifi-
cant decreases in calculated CLcr (p =
0.027) and GFR (p < 0.001).
Nissen et al.28 enrolled 309 pa-
tients with elevated triglyceride levels
and low high-density-lipoprotein
cholesterol values in a 12-week, ran-
domized controlled trial evaluating
the efficacy of the Eli Lilly investi-
gational PPARa agonist, LY518674.
Patients were randomized to receive
fenofibrate 200 mg daily, LY518674,
or placebo. Both fenofibrate and
LY518674 significantly increased
SCr concentrations compared with
placebo (p ≤ 0.001), with 38% and
37.3% of patients exceeding the up-
per limit of normal, respectively,
compared with 10.2% of patients
taking placebo. These results halted
development of LY518674 and raised
more safety concerns about feno-
fibrate and renal dysfunction. This
prospective study supported the
findings of the FIELD trial,16 which
found fenofibrate-induced elevations
in SCr levels in patients with normal
kidney function.
A double-blind, crossover,
placebo-controlled trial evaluated
the effect of fenofibrate on kidney
function in 21 volunteers with normal
kidney function (CLcr of ≥80 mL/min,
SCr concentration of <1.5 mg/dL).29
No concomitant medications were
allowed. Volunteers were random-
ized to fenofibrate 160 mg daily or
placebo for six weeks followed by a
two-week washout period and six
weeks of the alternative therapy. The
primary outcome of the study was
change in inulin clearance; secondary
outcomes included aminohippurate
sodium clearance, SCr concentra-
tion, CL cr, and urine creatinine
level. None of the participants had
diabetes mellitus, kidney disease, or
hypertension. Inulin clearance did
not change significantly after six
weeks of fenofibrate compared with
placebo (treatment difference, 0.8
mL/min; 95% confidence interval
[CI], –10.5 to 12.2 mL/min; p = 0.9).
Aminohippurate sodium and CLcr
values significantly decreased, while
SCr concentrations increased in par-
ticipants receiving fenofibrate versus
placebo (treatment difference, 0.11
mg/dL; p < 0.05). Urinary creatinine
excretion increased initially but was
unchanged after six weeks. Short-
term fenofibrate use did not appear
to alter GFR in these healthy partici-
pants. However, the study was short
in duration and did not include pa-
tients with preexisting renal disease.
In the ACCORD trial, the mean
SCr concentration for patients re-
ceiving fenofibrate increased from
0.93 to 1.10 mg/dL within the first
year of receiving the study drug; the
statistical significance of this finding
was not reported.17 The study proto-
col required dosage deescalation for
patients with a decreased estimated
GFR. Patients were given fenofibrate
160 mg if they had an estimated GFR
of ≥50 mL/min/1.73 m2 or 54 mg for
an estimated GFR between 30 and
50 mL/min/1.73 m2. Fenofibrate was
permanently discontinued if patients
developed an estimated GFR of <30
mL/min/1.73 m2. SCr concentration
was monitored every four months,
and the fenofibrate dosage was ad-
justed as appropriate. Fenofibrate
was permanently discontinued in 66
patients (2.4%) taking fenofibrate
compared with 30 patients (1.1%)
receiving placebo due to a low GFR.
The ACCORD Renal Ancillary
Study, a prospective substudy of
the ACCORD trial, evaluated three
groups of patients after trial comple-

tion to ascertain if elevations in SCr
levels associated with fenofibrate are
reversible.30 The groups included pa-
tients on fenofibrate with an increase
of ≥20% in SCr concentration after
three months of treatment (n = 321,
cases), patients taking fenofibrate
who had an increase of ≤2% in SCr
concentration (n = 175, controls),
and patients taking placebo (n =
565). After a median of 51 days after
discontinuation of fenofibrate, SCr
concentrations did decrease from 1.1
to 0.97 mg/dL (mean ± S.D. decrease
of 0.13 ± 0.01 mg/dL) in case pa-
tients. SCr concentrations were sig-
nificantly higher in case patients than
in the control group (p = 0.008). The
greatest decrease in SCr level from
trial end to the last substudy visit
occurred in the case patients (p =
0.002), with case patients attaining
SCr values similar to those patients
who received placebo (p = 0.3). Serum
cystatin C concentrations, used to es-
timate GFR, followed the same trend.
Patients who received full-dose
fenofibrate (160 mg) in the ACCORD
trial and experienced an increase of
≥20% in SCr concentration after four
months of fenofibrate therapy were
retrospectively evaluated to identify
risk factors for fenofibrate-associated
creatinine increases (FACIs).31 Of the
2523 patients randomized to receive
fenofibrate, 48% met criteria for
FACIs at four months. A multivari-
able regression model demonstrated
that patients who developed FACIs
were more likely to be older, be male,
have a longer duration of diabetes,
have a history of cardiovascular dis-
ease, and be concurrently receiving
angiotensin-converting-enzyme in-
hibitors, loop or thiazide diuretics, or
thiazolidinediones (p < 0.05 for all).
Interestingly, patients who developed
FACIs were also more likely to have
a lower baseline SCr concentration
(p < 0.0001), a finding that contrasts
with those of previous studies in
which patients with renal insuffi-
ciency had an increased risk of toxic-
ity. There was no difference between
clinical Consultation  Fenofibrate
groups in the development of micro-
albuminuria or macroalbuminuria
or in cardiovascular outcomes.
Population-based cohort study.
A population-based cohort study
evaluated 80,903 elderly patients
(age 66 years or older) in Canada
who had received a prescription for
fenofibrate or ezetimibe in the past
90 days.32 The primary outcome was
hospitalization due to increased SCr
levels. Patients treated with fenofi-
brate were significantly more likely to
be hospitalized for an increase in SCr
values (adjusted odds ratio, 2.4; 95%
CI, 1.7–3.3) and were more likely to
require a nephrologist consultation
(adjusted odds ratio, 1.3 [95% CI,
1.0–1.6]). The need for dialysis for
severe acute kidney injury and all-
cause mortality were similar between
groups. Patients with chronic kidney
disease were more likely to experi-
ence the primary outcome than those
who did not have chronic kidney
disease (p = 0.04). The authors noted
that patients included in this study
were more likely to be receiving high-
er dosages of fenofibrate compared
with the renally adjusted doses used
in previous studies (e.g., ACCORD
trial).17,32
Potential mechanisms of
nephrotoxicity
Several hypotheses regarding
the mechanism of fenofibrate-
associated nephrotoxicity have been
described.19-21,23,25,29 While the mech-
anisms may be biologically plausible,
none of the theories have been tested
in clinical trials.
One hypothesis theorizes that
fenofibrate may impair the genera-
tion of vasodilatory prostaglandins,
leading to decreased dilation of the
afferent arteriole and compromised
glomerular capillary pressure and
perfusion of the kidneys.19,22,23 Bind-
ing to PPAR receptors alters gene
transcription of an enzyme respon-
sible for converting arachidonic acid
to 20-hydroxyeicosatetranoic acid,
a product that inhibits the sodium–
Am J Health-Syst Pharm—Vol 70 Jul 15, 2013
potassium–chloride transporter in
the thick ascending loop of Henle.20,23
Another possibility is that fenofi-
brate may competitively inhibit se-
cretion of creatinine in the proximal
tubular lumen.20,21,29 Aminohippu-
rate sodium , a marker of glomerular
secretion, was significantly decreased
in the study by Ansquer and col-
leagues.29 However, no significant
difference was found in aminohip-
purate sodium clearance between
treatment groups in the Hottelart et
al. studies.25,26 Also, aminohippurate
sodium is secreted along the proxi-
mal tubule through organic anion
transport. Fenofibric acid has re-
cently been found to inhibit organic
anion transport, further confound-
ing the issue.29
An additional theory is that fen-
ofibrate may cause an increase in
endogenous creatinine production.25
There may be cross-reactivity be-
tween fenofibrate or its metabolites
and the assay used to measure cre-
atinine. This theory seems unlikely,
given that the effect is not seen in all
patients and there was no significant
difference between SCr values when
measured by both HPLC and the
Jaffe reaction.21,25,27
Reports of fibrate-related nephro-
toxicity are not limited to fenofibrate;
ciprofibrate and bezafibrate have
also been implicated.19,33 Agonism
of the particular PPAR subtype may
determine the risk of nephrotoxicity.
Reports of gemfibrozil causing neph-
rotoxicity are rare, even with numer-
ous patient-years of use, potentially
because the drug is a selective agonist
of PPARa. 19,33 Unlike gemfibro-
zil, fenofibrate is a full agonist of
PPARa. Tesaglitazar, a dual PPARa
and PPARg agonist, was withdrawn
from development due to the high
rate of renal impairment associated
with its use.18 Muraglitazar, another
dual PPARa and PPARg agonist, was
not approved by FDA due to data
that linked its use to an increased
frequency of death, major cardiovas-
cular adverse events, and congestive
1223
 clinical consultation  Fenofibrate
heart failure.34 The efficacy studies
for muraglitazar did not address
nephrotoxicity. Thiazolidinediones,
which are PPARg agonists, had not
been linked to the development
of nephrotoxicity until the recent
ACCORD substudy.31
Clinical relevance
The definition of fenofibrate-
associated nephrotoxicity varied
greatly in the studies reviewed herein.
In the study by Broeders and col-
leagues,19 nephrotoxicity was defined
as a change in SCr concentration of
at least 0.2 mg/dL, an increase that
typically would not warrant action
in clinical practice. Other studies
defined nephrotoxicity as a change
of ≥20% in SCr level.30,31 Despite
the inconsistencies in definition,
recent data support that even small
increases in SCr are associated with
increased patient mortality; there-
fore, more stringent definitions may
enable early detection.35,36
Fenofibrate-associated nephro-
toxicity was shown to be reversible
with both discontinuation and con-
tinued use of fenofibrate.29,30,32 The
typical time frame for reversal of el-
evated SCr levels varied among stud-
ies, from several days to months after
the use of fenofibrate.16,20,30 However,
one study found that the increase in
SCr values could be permanent, with
six patients having a persistent eleva-
tion over the study duration.19
Patients with baseline renal insuf-
ficiency may have an increased risk
of developing fenofibrate-associated
nephrotoxicity. Several studies found
that patients with chronic kidney
disease, renal transplant recipients,
and elderly patients had a higher
rate of fenofibrate-induced nephro-
toxicity.19,32,33 In addition, the use of
high-dosage fenofibrate, especially
in patients with renal dysfunction,
was associated with an increased rate
of nephrotoxicity.32,33 These find-
ings highlight the importance of
appropriate dosage adjustments for
patients with renal dysfunction.
1224 Am J Health-Syst Pharm—Vol 70 Jul 15, 2013
Lastly, several different formula-
tions of fenofibrate exist. The two
largest trials to examine the ef-
ficacy of fenofibrate (FIELD and
ACCORD) used micronized fenofi-
brate for the study drug. However,
there have been no data to link the
formulation of fenofibrate with the
occurrence of nephrotoxicity.16,17
Until more definitive data are avail-
able, clinicians utilizing fenofibrate in
their patients should evaluate base-
line SCr concentration and routinely
monitor this concentration in patients
using fenofibrate, particularly those
with baseline renal insufficiency and
renal transplant recipients. The use
of fenofibrate in patients with an es-
timated GFR of <30 mL/min/1.73 m2
may not be appropriate. Large data-
base reviews and prospective research
on patients receiving fenofibrate
therapy are essential to identify the
incidence and describe fenofibrate-
associated nephrotoxicity.
Conclusion
Fenofibrate-associated nephro-
toxicity is an underrecognized ad-
verse drug reaction. Several pub-
lished reports have detailed possible
etiologies; however, data detailing
the true incidence of fenofibrate-
associated nephrotoxicity and its as-
sociated risk factors are limited.
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