Fenofibrate-associated nephrotoxicity: A review of current evidence

The World Health Organization has defined an adverse drug reaction as a “response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of a disease.”¹ Many adverse reactions are not recognized at the time of drug approval. Studies of investigational drugs generally include limited populations with specific inclusion and exclusion criteria. Prescribers, however, utilize drugs in much larger and more heterogeneous populations, emphasizing the importance of postmarketing surveillance.

Fenofibrate is used in the treatment 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 prescribing information when the drug was first approved.^6,–8 Since drug approval, case reports as well as retrospective and prospective studies have reported fenofibrate-associated nephrotoxicity. However, the adverse effect is underrecognized in the clinical setting.⁹

Clinical use of fenofibrate

Fenofibrate, a fibric acid derivative, was approved by the Food and Drug Administration (FDA) in 1998 for the treatment of hypertriglyceridemia and atherogenic dyslipidemia.^3–5,8 Fenofibrate is a synthetic ligand that activates peroxisome proliferator-activated receptor α (PPARα), leading to changes in lipid metabolism, glucose homeostasis, and insulin resistance.^{3–5,10–12} Fenofibrate 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 cardiovascular outcomes has been assessed 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 significant improvements in the surrogate outcomes of minimum luminal narrowing (p = 0.029) and progression 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 fenofibrate 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 fenofibrate or placebo for a mean duration 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 tolerated by most patients^3,–5; however, fenofibrate may cause rare but serious adverse effects, including cholelithiasis and pancreatitis.^3,4,6–8,18 Nephrotoxicity, another serious adverse reaction associated with fenofibrate therapy, has been reported with increasing frequency.³, ¹², ¹⁹

Literature review

A MEDLINE search (1950 to May 2012) was conducted using the keywords fenofibrate and nephrotoxicity and MEDLINE Subject Heading terms procetofen; kidney diseases; kidney 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 retrospectively 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. Fenofibrate 100–200 mg daily was used by 25 patients; bezafibrate and ciprofibrate were used in 1 patient each. The transplant recipients were concurrently receiving immunosuppressive medications, including cyclosporine.

Patients’ baseline SCr concentration 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 discontinuation. 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 transplant recipients had a permanent increase in SCr level. In addition, 1 patient developed acute renal failure requiring hemodialysis. No correlation 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 cyclosporine levels before or during fenofibrate therapy.

In 2001, Lipscombe and colleagues²⁰ conducted a retrospective review of 10 men who had a history of renal insufficiency and received fibrate 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 concentration during fibrate therapy was 2.8 ± 0.2 mg/dL (p < 0.001 versus baseline), 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 concentration 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 studies suggest that increases in SCr levels are possible with fibrate therapy if patients have preexisting renal injury.^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 Nabulsi²¹ reported a case series of six patients whose SCr levels increased after the initiation 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 discontinuation. 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 obtaining a baseline SCr concentration and performing routine monitoring every one to two months in patients receiving fenofibrate.

Paul and Mohan²² examined fenofibrate-associated nephrotoxicity 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 experienced an increase in SCr concentration during therapy. The degree of SCr concentration increase was not reported for the second review. The investigators concluded that fenofibrate had no significant effect in patients with normal renal function but should not be used in patients with renal disease. This recommendation 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 nephrotoxicity. Patients received fenofibrate 54–67 mg daily for hyperlipidemia secondary to immunosuppressive medications. The baseline SCr concentration ranged from 1 to 2 mg/dL, and the peak SCr concentration 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 discontinued 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 concentrations and revealed evidence of proximal 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 Hispanic 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 increased from 3 and 25 mg/dL to 3.5 and 30 mg/dL, respectively, with a corresponding decrease in glomerular filtration rate (GFR) from 24.8 to 17.9 mL/min/1.73 m². After four weeks of therapy, his SCr concentration increased to 3.7 mg/dL, a 23% increase from baseline. The dosage was increased from 48 to 145 mg daily due to persistently elevated triglyceride levels, and the patient’s SCr concentration increased further to 4.7 mg/dL. Fenofibrate was discontinued; four days later, his SCr concentration decreased to 3.3 mg/dL without hemodialysis. The patient’s SCr concentration continued 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 parallel 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 concentration of ≥0.3 mg/dL within six months of initiating fenofibrate.²⁴ In a multivariable regression model, preexisting renal disease and initiation of high-dose fenofibrate were found to be independent predictors for the development of fenofibrate-associated nephrotoxicity.

Prospective studies

Hottelart and colleagues^25,26 enrolled patients with normal renal function or moderate chronic renal insufficiency and hyperlipidemia in a prospective study evaluating fenofibrate-associated nephrotoxicity. The trial was performed 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. Fenofibrate 200 mg daily or every other day was initiated if the estimated 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 aminohippurate sodium, inulin, and urine creatinine concentrations. In the second phase of the study, patients treated with fenofibrate had significantly 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 (CL_cr) was unchanged. A correlation was shown between the Jaffe reaction and HPLC, indicating that the increase in SCr concentration was not due to assay interference (r² = 0.675, p = 0.0006). These findings suggest that even though fenofibrate is associated with increased SCr levels, glomerular function may not be affected.

The FIELD trial was a multinational, 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 impairment (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 receiving placebo had no change in SCr value. In addition, 73 patients (2%) taking fenofibrate versus 48 patients (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 discontinuation. 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 during fenofibrate therapy was not accompanied by an increase in urinary creatinine but did translate to significant decreases in calculated CL_cr (p = 0.027) and GFR (p < 0.001).

Nissen et al.²⁸ enrolled 309 patients with elevated triglyceride levels and low high-density-lipoprotein cholesterol values in a 12-week, randomized controlled trial evaluating the efficacy of the Eli Lilly investigational PPARα 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 upper limit of normal, respectively, compared with 10.2% of patients taking placebo. These results halted development of LY518674 and raised more safety concerns about fenofibrate 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 (CL_cr of ≥ 80 mL/min, SCr concentration of <1.5 mg/dL).²⁹ No concomitant medications were allowed. Volunteers were randomized 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 concentration, 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 CL_cr values significantly decreased, while SCr concentrations increased in participants 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 participants. However, the study was short in duration and did not include patients with preexisting renal disease.

In the ACCORD trial, the mean SCr concentration for patients receiving 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 protocol 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 adjusted 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 completion to ascertain if elevations in SCr levels associated with fenofibrate are reversible.³⁰ The groups included patients 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 patients. SCr concentrations were significantly 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 estimate 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 multivariable 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 disease, and be concurrently receiving angiotensin-converting-enzyme inhibitors, 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 insufficiency had an increased risk of toxicity. There was no difference between 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 fenofibrate 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 experience 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 higher 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 mechanisms may be biologically plausible, none of the theories have been tested in clinical trials.

One hypothesis theorizes that fenofibrate may impair the generation of vasodilatory prostaglandins, leading to decreased dilation of the afferent arteriole and compromised glomerular capillary pressure and perfusion of the kidneys.¹⁹, ²², ²³ Binding to PPAR receptors alters gene transcription of an enzyme responsible for converting arachidonic acid to 20-hydroxyeicosatetranoic acid, a product that inhibits the sodium–potassium–chloride transporter in the thick ascending loop of Henle.^20,23

Another possibility is that fenofibrate may competitively inhibit secretion of creatinine in the proximal tubular lumen.²⁰, ²¹, ²⁹ Aminohippurate sodium, a marker of glomerular secretion, was significantly decreased in the study by Ansquer and colleagues.²⁹ However, no significant difference was found in aminohippurate sodium clearance between treatment groups in the Hottelart et al. studies.^25,26 Also, aminohippurate sodium is secreted along the proximal tubule through organic anion transport. Fenofibric acid has recently been found to inhibit organic anion transport, further confounding the issue.²⁹

An additional theory is that fenofibrate may cause an increase in endogenous creatinine production.²⁵ There may be cross-reactivity between fenofibrate or its metabolites and the assay used to measure creatinine. 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 nephrotoxicity 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 nephrotoxicity are rare, even with numerous patient-years of use, potentially because the drug is a selective agonist of PPARα.^19,33 Unlike gemfibrozil, fenofibrate is a full agonist of PPARα. Tesaglitazar, a dual PPARα and PPARγ agonist, was withdrawn from development due to the high rate of renal impairment associated with its use.¹⁸ Muraglitazar, another dual PPARα and PPARγ agonist, was not approved by FDA due to data that linked its use to an increased frequency of death, major cardiovascular adverse events, and congestive heart failure.³⁴ The efficacy studies for muraglitazar did not address nephrotoxicity. Thiazolidinediones, which are PPARγ 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 colleagues,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; therefore, more stringent definitions may enable early detection.^35,36

Fenofibrate-associated nephrotoxicity was shown to be reversible with both discontinuation and continued use of fenofibrate.²⁹, ³⁰, ³² The typical time frame for reversal of elevated SCr levels varied among studies, 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 elevation over the study duration.¹⁹

Patients with baseline renal insufficiency 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 nephrotoxicity.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 findings highlight the importance of appropriate dosage adjustments for patients with renal dysfunction.

Lastly, several different formulations of fenofibrate exist. The two largest trials to examine the efficacy of fenofibrate (FIELD and ACCORD) used micronized fenofibrate 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 available, clinicians utilizing fenofibrate in their patients should evaluate baseline 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 estimated GFR of <30 mL/min/1.73 m² may not be appropriate. Large database reviews and prospective research on patients receiving fenofibrate therapy are essential to identify the incidence and describe fenofibrate-associated nephrotoxicity.

Conclusion

Fenofibrate-associated nephrotoxicity is an underrecognized adverse drug reaction. Several published reports have detailed possible etiologies; however, data detailing the true incidence of fenofibrate-associated nephrotoxicity and its associated risk factors are limited.

Footnotes

References