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Reversibility of Fenofibrate Therapy - Induced Renal Function Impairment in ACCORD Type 2 Diabetic Participants
Reversibility of Fenofibrate Therapy - Induced Renal Function Impairment in ACCORD Type 2 Diabetic Participants
O R I G I N A L A R T I C L E
F
JOSYF C. MYCHALECKYJ, DPHIL1 DANIEL LORBER, MD7 enofibrate therapy is commonly pre-
TIMOTHY CRAVEN, MS2 SANTICA MARCOVINA, PHD8 scribed for the clinical management
UMA NAYAK, PHD1 WILLIAM SIVITZ, MD9 of elevated triglyceride levels in dia-
JOHN BUSE, MD3 JOANN SPERL-HILLEN, MD10 betic patients, but has been noted to cause
JOHN R. CROUSE, MD4 DENISE E. BONDS, MD11
MARSHALL ELAM, MD, PHD5 HENRY N. GINSBERG, MD12 an elevation in serum creatinine concen-
KENT K IRCHNER, MD6 trations. In several small studies, creatinine
levels increased during fenofibrate treatment
but returned to baseline after discontinua-
tion of therapy (1–4). In the Diabetes Ath-
offered a rare opportunity in a large cohort case subjects (“cases”) were defined as ac- assay sensitivity was 0.03 mg/dL, and intra-
to determine if the rise in creatinine seen tive participants in the fenofibrate arm assay coefficients of variation based on
among some individuals upon starting who had experienced $20% increase in analysis of low- and high-quality control
fenofibrate is reversible after prolonged serum creatinine from trial baseline to samples were 0.8% and 0.7%, respectively,
exposure to the drug. month 4 and remained on study medica- while interassay coefficients of variation were
tion at close out (either full or reduced 1.6% and 2.5%. The interassay precision is
RESEARCH DESIGN AND dose). Since the study drug was started consistently ,1.4% for the high-quality
METHODSdThe ACCORD Trial was a 1-month postrandomization, study month and ,2.2% for the low-quality control sam-
double 2 3 2 factorial trial designed 4 was equivalent to 3 months of therapy. ples. Serum cystatin C concentrations were
to test the effect of 1) intensive glucose Fenofibrate arm control subjects (“controls”) determined using the Siemens Diagnostics
control versus standard control, 2) inten- were defined as active in the fenofibrate reagent on a Roche Hitachi P-Module an-
sive blood pressure control versus stan- arm who experienced #2% increase in cre- alyzer (Siemens Diagnostics, Deerfield, IL).
dard control, and 3) lipid treatment atinine over the same period. Placebo arm The interassay precision for the high- and
strategy that used fenofibrate plus a statin control subjects (“placebos”) were defined low-quality control samples was 2.5 and
compared with statin monotherapy on as randomized to placebo but without re- 2.6%, respectively. All serum samples were
the composite outcome of myocardial in- striction on their change in serum creati- analyzed for creatinine on the day of sample
farction, stroke, or cardiovascular death. nine. Individuals with baseline renal receipt; cystatin C assays were performed in a
controls. Observed variability was less than were deaths with causes not attributed to (55%) or placebos (49%); differences
projected, yielding post hoc power esti- this study. The clinical characteristics for among all three groups in the mean follow-
mates of 99% for all three comparisons. the three recruited study groups are listed up time during the main trial from ran-
in Table 1. As expected, the change in se- domization to close-out visit (5.0 6 1.0 vs.
RESULTSdWe recruited 321 active rum creatinine between the trial baseline 5.6 6 1.6 vs. 5.2 6 1.2 years); more Asian
fenofibrate arm cases (30.2%), 175 active and month 4 visits was significantly differ- participants among controls (17%) than in
fenofibrate arm controls (16.5%), and 565 ent between cases and controls with a mean cases (10%) or placebo (10%); a lower tri-
active placebo controls (53.3%) plus 20 (6 SD) increase of +0.31 6 0.16 mg/dL in glyceride level at trial close-out among
others (18 ineligible and 2 eligible but cases, decrease of 20.05 6 0.08 mg/dL in cases (136 6 14 mg/dL) than either controls
missing required study data) for a total controls, and was also significantly differ- (160 6 227 mg/dL) or placebos (163 6 93
ACCORD Renal Ancillary Study enroll- ent between controls and placebos, with mg/dL); greater use of insulin by cases at trial
ment of 1,081 participants. Forty-nine placebos showing no change (0.00 6 close-out (62%) than among controls
individuals (4.6%) were lost to follow-up 0.13 mg/dL). Other differences between (49%); and more cases (58%) with a creat-
between the trial close-out visit (the first the three groups included fewer control inine .1.0 mg/dL at close-out than among
Renal Study on-drug visit) and postclose- participants in the intensive arm of the either controls (38%) or placebos (36%).
out (off-drug) visit. Two of the forty-nine ACCORD Glycemia Trial (37%) than cases There were no significant differences in
mean time interval between close-out treatment arm assignment, age, diabetes of the entire eligible ACCORD Lipid Trial
and postclose-out visits for the three duration, sex, nonwhite race, insulin use, cohort at month 4.
groups (Table 2). Creatinine levels in ca- and systolic and diastolic blood pressure; In the retrospectively defined nested
ses remained higher than controls at the change in values were additionally ad- groups, the mean (6 SE) serum creatinine
study close-out after a mean of 5.2 years justed for the time interval between visits at the month 4 visit was greater in cases
of follow-up, although the creatinine (trial baseline to month 4, or trial close- (1.16 6 0.01 mg/dL) than in controls
levels in cases declined from the month out to postclose-out visit). All subsequent (0.90 6 0.01 mg/dL) or placebos (0.90 6
4 visit to close-out visit, while that of the results in the main text refer to these ad- 0.01 mg/dL). No difference was seen be-
controls and placebos increased, nar- justed values (unadjusted values are in- tween controls and placebos (P = 0.9). At
rowing the difference in the means be- cluded for comparison in Supplementary the trial close-out visit after a mean trial
tween the groups. Table 1). The mean serum creatinine levels follow-up period of 5.2 years (range
Table 2 shows the adjusted mean cre- in the three study groups were not signifi- 5.0–5.6 years in the three groups), serum
atinine and eGFR for the three groups at cantly different at baseline or month 4 from creatinine was still greater in cases than
four time points during the trial and the the other participants in the main lipid trial controls or placebos (1.11 6 0.02 mg/dL
postclose-out visit. The same data are who would have satisfied the retrospective versus 1.01 6 0.02 mg/dL and 0.98 6 0.01
plotted in Figs. 1A and 2A. The mean val- percent change in serum creatinine inclu- mg/dL, respectively) although the difference
ues in Table 2 were adjusted for glycemia sion criterion and were thus representative in the means of the three groups decreased.
CONCLUSIONSdWe investigated
the potential reversibility of the rapid se-
rum creatinine increase observed on start-
ing fenofibrate therapy. The fenofibrate
cases (participants who experienced a 20%
or more increase in serum creatinine after 3
months of fenofibrate; 47.4% of all partic-
ipants randomized to fenofibrate in the
ACCORD Lipid Trial) had a mean serum cre-
atinine decrease on cessation of fenofibrate
to a value that was no different than the
mean creatinine of the placebo reference
group, suggesting no residual loss of GFR
after 5 years of therapy. This reversal of
serum creatinine elevation was complete
after 51 days off therapy. By contrast, for
the control subgroup of fenofibrate par-
Figure 2dTime course values of adjusted eGFR and cGFR by ACCORD Renal Study Group. A:
The changes in eGFR in units of mL/min/1.73 m2. B: Changes in cGFR in units of mL/min/1.73 m2. ticipants (participants who experienced
The horizontal trial time point axis is not shown to scale. The study group trends are shown as: ,2% change in creatinine; 24.6% of all
black circles, fenofibrate cases; red triangles, fenofibrate controls; blue crosses, placebo controls. participants randomized to fenofibrate),
Base, baseline visit; M4, month 4 visit; Close, close-out visit; Post, postclose-out visit. (A high- the mean serum creatinine was lower
quality color representation of this figure is available in the online issue.) than the placebo reference group after
51 days off therapy, suggesting a net pres- serum creatinine immediately after initi- increase in cystatin C levels accompanied
ervation of GFR and renal function. The ating therapy, which is expected in about the initial increase in serum creatinine with
serum cystatin C results showed similar 25% of patients with a similar profile to fenofibrate (12). The results suggest that
trends. ACCORD Lipid. A similar protective effect the physiological mechanism for the rapid
Fenofibrate was also found to have a on GFR was also seen in fenofibrate increase in serum creatinine on initiation
protective effect on the albuminuria levels participants more generally at the con- of fenofibrate therapy (and the reversion
in ACCORD Lipid Trial participants. Fewer clusion of the FIELD Trial (7). Whether on cessation) is not specific for creatinine
participants randomized to fenofibrate this preservation is maintained or whether and rule out increased creatinine pro-
progressed to frank microalbuminuria or it reduces the long-term macro- or mi- duction or secretion as a plausible mech-
proteinuria postrandomization than place- crovascular disease risk after the initial anism. However, more work needs to be
bos (16). This result is consistent with the 5 years of therapy is unknown. The done to confirm and elaborate these
reduced progression found in the DAIS and ACCORDION (ACCORD Follow-Up) findings.
FIELD Trials (5,7), and the greater reduc- Study, which is currently underway, An unexpected benefit of this design
tion in mean urinary albumin/creatinine will help to answer the second question. was that it highlighted the differences in
ratio in the fenofibrate arm compared ACCORDION is a posttrial, prospective, changes in serum creatinine and cystatin
with placebo over 5 years of follow-up in observational study of 8,000 ACCORD C in major subgroups of trial participants
FIELD (7). The ACCORD Lipid Trial albu- participants over 3.5 years to elucidate the once these subgroups ceased on-trial
less renal function loss compared with pla- No other potential conflicts of interest rel- 8. Keech A, Simes RJ, Barter P, et al.; FIELD
cebo over 5 years of therapy. More work evant to this article were reported. study investigators. Effects of long-term
needs to be done to test these findings over J.C.M. researched data and wrote the man- fenofibrate therapy on cardiovascular events
longer durations of therapy, to determine uscript. T.C. researched data and edited the in 9795 people with type 2 diabetes mellitus
manuscript. U.N. researched data. J.B., J.R.C., (the FIELD study): randomised controlled
if this apparent renal protection is also
E.M., K.K., and J.S.-H. contributed to discus- trial. Lancet 2005;366:1849–1861
seen among the low HDL/high triglycer- sion and reviewed the manuscript. D.L.,W.S., 9. Hottelart C, El Esper N, Rose F, Achard
ide subgroup that had apparent cardio- D.E.B., and H.N.G. contributed to discussion JM, Fournier A. Fenofibrate increases cre-
vascular benefit in the main ACCORD and reviewed and edited the manuscript. atininemia by increasing metabolic pro-
Lipid Study, and to determine the duration S.M. researched data, contributed to discus- duction of creatinine. Nephron 2002;92:
of the apparent renal protective effects. sion, and reviewed and edited the manu- 536–541
script. J.C.M. is the guarantor of this work 10. Ansquer JC, Dalton RN, Caussé E, Crimet
and, as such, had full access to all the data in D, Le Malicot K, Foucher C. Effect of
the study and takes responsibility for the fenofibrate on kidney function: a 6-week
AcknowledgmentsdThis investigator-initiated integrity of the data and the accuracy of the randomized crossover trial in healthy peo-
study was supported by a research grant from data analysis. ple. Am J Kidney Dis 2008;51:904–913
Abbott Laboratories (J.C.M. and T.C.). The Parts of this study were presented as an oral 11. Westphal S, Dierkes J, Luley C. Effects of
ACCORD Trial was supported by grants (N01- presentation at the 71st Scientific Sessions of fenofibrate and gemfibrozil on plasma
HC-95178, N01-HC-95179, N01-HC-95180, the American Diabetes Association, San Diego, homocysteine. Lancet 2001;358:39–40