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Preliminary Communication |

Effects of a Potent and Selective PPAR-α Agonist in Patients With Atherogenic Dyslipidemia or Hypercholesterolemia:  Two Randomized Controlled Trials FREE

Steven E. Nissen, MD; Stephen J. Nicholls, MBBS, PhD; Kathy Wolski, MPH; Daniel C. Howey, MD; Ellen McErlean, RN, MSN; Ming-Dauh Wang, PhD; Elisa V. Gomez, MS; John M. Russo, MD
[+] Author Affiliations

Author Affiliations: Department of Cardiovascular Medicine, Cleveland Clinic Lerner School of Medicine, Cleveland, Ohio (Drs Nissen and Nicholls and Mss Wolski and McErlean); Eli Lilly and Company, Indianapolis, Ind (Drs Howey and Wang and Ms Gomez); and Guilford Medical Associates and Moses Cone Health System, Greensboro, NC (Dr Russo).

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JAMA. 2007;297(12):1362-1373. doi:10.1001/jama.297.12.1362.
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Published online

Context Fibrates are weak agonists of peroxisome proliferator–activated receptor α (PPAR-α). No trials have reported effects of more potent and selective agents.

Objectives To examine the safety and efficacy of LY518674, a PPAR-α agonist.

Design, Setting, and Participants Two multicenter, randomized, double-blind, placebo-controlled trials: 1 in patients with elevated triglycerides and low HDL-C (atherogenic dyslipidemia), the other in patients with elevated LDL-C (hypercholesterolemia). Between August 2005 and August 2006, the dyslipidemia study randomized 309 patients at US centers; the hypercholesterolemia study, 304 patients.

Interventions Dyslipidemia study: placebo, fenofibrate (200 mg), or LY518674 (10, 25, 50, or 100 μg) for 12 weeks. Hypercholesterolemia study: placebo or atorvastatin (10 or 40 mg) for 4 weeks, then placebo or LY518674 (10 or 50 μg) for 12 more weeks.

Main Outcome Measures Dyslipidemia study: percentage change in levels of HDL-C and triglycerides. Hypercholesterolemia study: percentage change in levels of LDL-C.

Results Dyslipidemia study: LY518674 (25 μg) and fenofibrate increased HDL-C by 5.9 and 5.5 mg/dL (15.8% and 14.4%) (both P≤.001 vs placebo, P = .79 between treatments). Higher LY518674 doses yielded smaller increases. LY518674 decreased triglycerides by 97.3 to 114.5 mg/dL (34.9% to 41.7%) but was similar to fenofibrate. LY518674 produced a dose-dependent increase in LDL-C, reaching 20.4 mg/dL (19.5%) for the 100-μg dose vs 0.3 mg/dL (2.3%) for fenofibrate (P≤.01). Fenofibrate and LY518674 (50 μg and 100 μg) increased serum creatinine (P≤.001 vs placebo), with 38% and 37.3% of patients exceeding the normal range. Fenofibrate, but not LY518674, increased creatine phosphokinase (P = .004 vs placebo). Hypercholesterolemia study: LY518674 (10 μg or 50 μg) decreased LDL-C by 21.4 to 26.0 mg/dL (13.2%-15.8%) and triglycerides ≈37% for both doses, and increased HDL-C by 6.3 to 6.7 mg/dL (12.5%-15.0%). When added to atorvastatin, LY518674 changed HDL-C by −0.7 to 6.2 mg/dL (−0.6% to 11.9%) and significantly decreased triglycerides but had no additional effect on LDL-C.

Conclusions In patients with dyslipidemia, LY518674 and fenofibrate decreased triglycerides and increased HDL-C but also increased serum creatinine. LY518674, but not fenofibrate, increased LDL-C. In those with hypercholesterolemia, LY518674 reduced triglycerides and increased HDL-C, but did not further reduce LDL-C in combination with atorvastatin. Fenofibrate and LY518674 both raised safety concerns.

Trial Registration clinicaltrials.gov Identifiers: NCT00133380 and NCT00116519

Trial Registration Published online March 25, 2007 (doi:10.1001/jama.297.12.1362).

Figures in this Article

Fibric acid derivatives (fibrates) are among the oldest agents used to treat patients with lipid disorders.1 Clofibrate, the original agent in this class, was introduced in the 1960s but is now rarely prescribed. In current practice, 2 fibrates, gemfibrozil and fenofibrate, are widely used to treat a constellation of lipid abnormalities known as atherogenic dyslipidemia.24 The features of this syndrome comprise a cluster of risk factors that include elevated serum levels of triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C), and a more atherogenic form of low-density lipoprotein cholesterol (LDL-C), known as small-dense LDL-C.5 Fibrates markedly lower serum triglycerides levels and modestly increase levels of HDL-C. Two randomized controlled trials of gemfibrozil demonstrated a reduction in adverse cardiovascular outcomes, particularly in patients with atherogenic dyslipidemia.6,7

The mechanism of action of fibrates is mediated through modulation of the peroxisome proliferator-activated receptor α (PPAR-α).810 PPARs are ligand-activated nuclear transcription factors that modulate gene expression with major effects on lipid and glucose metabolism.9 However, currently available fibrates are weak ligands for the PPAR-α receptor and may interact with other PPAR systems. Accordingly, the pharmaceutical industry has sought to develop new, more potent and selective agents within this class. However, none of the novel PPAR-α agonists has achieved regulatory approval. According to a former safety officer in the US Food and Drug Administration (FDA), more than 50 PPAR agonists have been discontinued due to various types of toxicity.11 Nearly all of the new PPAR-modulating agents have been discontinued without scientific publications describing the reasons for termination of the development programs.

We conducted 2 randomized controlled trials to characterize a potent and selective PPAR-α agonist, known as LY518674, which is approximately 10 000 times more potent than fenofibrate.12,13 These initial studies assessed the safety and efficacy of this agent at varying doses as monotherapy or in combination with atorvastatin. This report represents the first published description of the potential benefits and risks of a novel, highly potent and selective PPAR-α agonist.

Study Design

The study design consisted of 2 separate trial protocols intended to evaluate the safety and efficacy of LY518674 in 2 populations, one with atherogenic dyslipidemia and the other with hypercholesterolemia. These 2 trials were multicenter, randomized, double-blind, double-dummy, sequential, parallel, placebo-controlled studies and were conducted concommitantly. The institutional review boards of all participating centers approved the protocols, and all patients provided written informed consent. Both protocols specified enrollment of patients between 18 and 80 years of age.

Atherogenic Dyslipidemia Study

In the atherogenic dyslipidemia study, patients were required to have an HDL-C level less than 45 mg/dL (1.2 mmol/L) for men or 50 mg/dL (1.3 mmol/L) for women, triglycerides levels between 150 mg/dL and 600 mg/dL (1.7 mmol/L and 6.8 mmol/L), and an LDL-C level of 160 mg/dL (4.1 mmol/L) or less. Statins were permitted, if clinically indicated, but investigators were instructed not to adjust doses during the trial.

Patients were excluded for poorly controlled diabetes defined as a glycosylated hemoglobin level of 8% or greater, or concomitant use of insulin or a thiazolidinedione. Patients were also excluded if they had laboratory measures of thyroid function outside of the normal range; had uncontrolled hypertension, defined as 3 separate measurements exceeding 160/95 mm Hg during screening; or were receiving treatment for congestive heart failure or had a known ejection fraction less than 35%. Patients were also excluded if their levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, or total bilirubin were greater than 1.5 times the upper limit of normal, if their serum creatinine levels were greater than 2 mg/dL (177 μmol/L), or if they had nephrotic syndrome, end-stage renal disease, and used renal replacement therapy such as hemodialysis or peritoneal dialysis.

All patients entered a 4-week placebo lead-in period to evaluate the effect of the National Cholesterol Education Program Therapeutic Lifestyle Changes diet.12 Patients with triglycerides levels less than 150 mg/dL (1.7 mmol/L) at the end of this period were not permitted to proceed to the active-treatment phase. During a 12-week active-treatment period, patients were randomized to receive treatment with LY518674 (10 μg, 25 μg, 50 μg, or 100 μg) (Eli Lilly and Co, Indianapolis, Ind), fenofibrate (200 mg) (Lofibra; Gates Pharmaceuticals, Sellersville, Pa), or placebo, stratified according to concomitant statin use.

Hypercholesterolemia Study

Entry criteria required an LDL-C level between 100 mg/dL and 160 mg/dL (2.6 mmol/L and 4.1 mmol/L) with concomitant statin therapy or between 130 mg/dL and 190 mg/dL (3.4 mmol/L and 4.9 mmol/L) in statin-naive patients. Exclusion criteria included the presence of diabetes, any clinical manifestation of coronary heart disease, abnormal thyroid function, heart failure, or uncontrolled hypertension. Patients were also excluded if their levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, or total bilirubin were greater than 1.5 times the upper limit of normal, if their serum creatinine levels were greater than 2 mg/dL (177 μmol/L), or if they had nephrotic syndrome, end-stage renal disease, and used renal replacement therapy such as hemodialysis or peritoneal dialysis.

Following a 4- to 6-week washout period, patients entered a 4-week active-treatment period during which they were randomized to receive placebo or atorvastatin (10 mg or 40 mg). These treatment groups were stratified on the basis of their LDL-C levels into groups with values less than or greater than 160 mg/dL. Patients subsequently entered a 12-week active treatment period during which those within each of the previous treatment groups were randomized to receive placebo or LY518674 (10 μg or 50 μg).

Clinic Visits and Laboratory Tests

Patients were examined during scheduled clinic visits every 1 to 2 weeks during the treatment phase and at a follow-up visit 2 to 4 weeks following cessation of the study drug. A central laboratory blinded to group assignment performed all biochemical determinations (Covance, Indianapolis, Ind). Lipoprotein levels were measured at 3 intervals during the follow-up period, while blood pressure and safety laboratory measurements were obtained at each study visit.

Statistical Analysis

In the atherogenic dyslipidemia study, the protocol prespecified 2 primary end points (percentage changes in levels of triglycerides and HDL-C from baseline to 12 weeks' follow-up). A sample size of 50 patients per group was selected to provide 90% power to detect a 23% decrease in triglycerides levels (assuming an SD of 35%) and to detect a 13% increase in HDL-C levels (assuming an SD of 20%) for the comparison of each dose of LY518674 with placebo (5% type I error rate for a 2-sided test).

In the hypercholesterolemia study, the prespecified primary end point was the additional effect on LDL-C levels of each dose of LY518674 compared with placebo in patients treated with atorvastatin. Power calculations required a sample size of 23 patients per group to provide 90% power (assuming an SD of 20%) to detect a 20% change in levels of LDL-C (comparing LY518674 with placebo), with a 2-sided test and type I error rate of 5%. Assuming a dropout rate of approximately 30%, enrollment of 300 patients was specified.

Demographic and laboratory characteristics are summarized for all randomized patients taking at least 1 dose of study drug, defined as the intention-to-treat population. Categorical variables are described using frequencies, while continuous variables are reported as mean and SD or as median and interquartile range. The efficacy analyses were performed on all patients in the intention-to-treat population in whom a baseline value and at least 1 postbaseline measurement were available. The analysis of safety was performed for all intention-to-treat patients. Laboratory safety measures are reported as the change from baseline area under the curve for all values to end-of-treatment, divided by the duration of the period (AUC/t).

In the hypercholesterolemia study, the efficacy population excluded patients taking nonstudy lipid-lowering medications during the trial. The methods prespecified a likelihood function–based inference using a mixed model for repeated measures, using all available follow-up data for results with more than 1 postbaseline measurement (a compound symmetry covariance structure was assumed). Imputation of missing data was not considered in the primary analysis. Last observation carried forward was used for those results with only 1 postbaseline measurement. For the analysis of the percentage change in lipids levels, the logarithm of the ratio from end point to baseline was used as a dependent variable. For C-reactive protein level and blood pressure, the change from end point to baseline was analyzed as the dependent variable.

For the atherogenic dyslipidemia study, the model controlled for the baseline value, statin use (yes or no), age (<55 vs ≥55 years), treatment, visit, and treatment × visit interaction. For the hypercholestolemia study, the model controlled for baseline value, atorvastatin dose, LY518674 dose, visit, and all interactions between visit and dose group for atorvastatin and LY518674. For blood pressure and levels of apolipoproteins, age was also included in the model as a covariate. Analyses were performed using SAS version 8.2 (SAS Institute Inc, Cary, NC); P >.05 was used to determine statistical significance.

Participants

Between August 10, 2005, and August 22, 2006, 309 patients were enrolled in the atherogenic dyslipidemia study. The disposition of these patients is shown in Figure 1. Between August 29, 2005, and May 10, 2006, 304 patients were randomized in the hypercholesterolemia study. The disposition of these patients is shown in Figure 2.

Figure 1. Disposition of Patients in the Atherogenic Dyslipidemia Study
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Figure 2. Disposition of Patients in the Hypercholesterolemia Study
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The baseline characteristics of the patients in the atherogenic dyslipidemia population are shown in Table 1. Characteristics were similar for all treatment groups and are therefore presented in a summary fashion. The mean age was 54 years, and approximately 70% of patients were men. Most patients were obese, with a mean body mass index exceeding 32 (calculated as weight in kilograms divided by height in meters squared). As anticipated by the entry criteria, triglycerides levels were substantially elevated, with a median value approaching 250 mg/dL (2.8 mmol/L), and HDL-C levels were low, averaging less than 40 mg/dL (1.0 mmol/L). Approximately 40% of patients were taking statin drugs at baseline.

Table Graphic Jump LocationTable 1. Baseline Demographic Characteristics and Biochemical Parameters (Safety Population)

The baseline characteristics of the patients in the hypercholesterolemia study are also shown in Table 1. Characteristics were similar for all treatment groups and are presented in a summary fashion. The mean age was 54 years, and approximately half of the study participants were men. Body mass index averaged 29.4. As anticipated by the entry criteria, levels of total cholesterol and LDL-C were elevated (248 mg/dL and 164 mg/dL [6.4 mmol/L and 4.2 mmol/L], respectively). Levels of HDL-C were relatively normal, averaging 49.6 mg/dL (1.3 mmol/L).

Lipoprotein Effects: Atherogenic Dyslipidemia Study

Table 2 reports the effects of LY518674 in the atherogenic dyslipidemia study. Both fenofibrate and LY518674 markedly decreased triglycerides levels. For fenofibrate, the reduction was 32.8%, with 95% confidence intervals ranging from 24.8% to 39.9%. LY518674 produced similar reductions, ranging from 34.9% to 41.7%, which were not statistically different from the effect produced by fenofibrate, although there were not statistically significant greater reductions for the 50-μg dose of LY518674 (41.7%; P = .08 compared with fenofibrate). Fenofibrate increased HDL-C levels by 14.4% (95% confidence interval, 7.5%-21.8%). LY518674 showed an unusual dose-response pattern, with the lowest dose (10 μg) producing a modest increase (9.6%) in HDL-C levels, a maximum increase of 15.8% occurring at the 25-μg dose, and lesser increases with higher dosages. The 100-μg LY518674 dose produced a 2.1% increase in levels of HDL-C, which was not significantly different from the effect produced by placebo and smaller when compared with fenofibrate (P = .01).

Table Graphic Jump LocationTable 2. Atherogenic Dyslipidemia Study: Absolute and Percentage Changes in Laboratory Parameters and Blood Pressure From Baseline Until Follow-up Visit

LY518674 increased levels of LDL-C in this population. The least-square mean percentage increase was 2.3% for fenofibrate but was significantly greater for the 50-μg and 100-μg LY518674 doses, 18.3% and 19.5%, respectively (both P≤.001 compared with placebo and P = .002 compared with fenofibrate). Apolipoprotein (Apo) A-1 levels increased parallel to the increases in HDL-C levels, but Apo A-II levels showed a strong positive dose-response relationship for LY518674, with the increase reaching 30.0% for the 100-μg LY518674 dose.

Lipoprotein Effects: Hypercholesterolemia Study

Table 3 reports the effects of LY518674 as monotherapy; Table 4 reports the effects of LY518674 when added to atorvastatin in patients with hypercholesterolemia. As monotherapy, LY518674 (10 μg and 50 μg) reduced triglycerides levels by 36.9% and 37.5% (P≤.001) and increased HDL-C levels by 15.0% and 12.5%, respectively. Given without atorvastatin, LY518674 (10 μg and 50 μg) decreased LDL-C levels by 13.2% and 15.8%, respectively. When added to atorvastatin, LY518674 (10 μg and 50 μg) produced statistically significant additional decreases in levels of triglycerides, ranging from 20.4% to 42.7%, respectively, depending on the LY518674 and atorvastatin doses. As shown in Table 4, when added to atorvastatin (10 mg), HDL-C levels increased 9.8% for LY518674 (10 μg) and 11.9% for LY518674 (50 μg). When added to atorvastatin (40 mg), HDL-C levels increased 9.2% for LY518674 (10 μg) and 0.6% for LY518674 (50 μg). When added to either atorvastatin dose, LY518674 (10 μg and 50 μg) produced no statistically significant additional reductions in LDL-C levels beyond that provided by atorvastatin alone.

Table Graphic Jump LocationTable 3. Hypercholesterolemia Study: Absolute and Percentage Changes in Laboratory Parameters and Blood Pressure From Baseline Until Final Follow-up Visit
Table Graphic Jump LocationTable 4. Hypercholesterolemia Study: Additional Effects of LY518674 After Randomization to Atorvastatin (Percentage Change From 4 Weeks to End of Treatment)
Safety Assessment

Laboratory safety measures are shown in Table 5 and Table 6. In the dyslipidemia study, administration of LY518674 at the higher dose levels of 50 μg and 100 μg, or administration of fenofibrate, increased the AUC/t in levels of serum creatinine (P≤.001 compared with placebo). Many patients experienced increases in creatinine levels that resulted in values exceeding the upper limits of normal. Fenofibrate, but not LY518674, increased the AUC/t in creatinine phosphokinase measurements (P = .004).

Table Graphic Jump LocationTable 5. Atherogenic Dyslipidemia Study: Laboratory Safety Parameters*
Table Graphic Jump LocationTable 6. Hypercholesterolemia Study: Laboratory Safety Parameters*

There was no consistent pattern to other adverse events, however, in the hypercholesterolemia study; 16.7% of patients receiving atorvastatin (40 mg) with LY518674 (50 μg) had alanine aminotransferase levels between 1.5 and 3 times the upper limit of normal (P = .10 compared with placebo). In addition to the laboratory values reported in Tables 5 and 6, levels of troponin I were also measured during both trials and showed no significant increases for fenofibrate or LY518674. Investigator-reported adverse events were rare and showed no consistent pattern.

Treatment to reduce levels of LDL-C represents a primary goal for prevention of cardiovascular disease.14 However, many patients experience adverse cardiovascular outcomes despite treatment to lower LDL-C levels, a phenomenon often attributed to the increasing prevalence of obesity and related factors, including hypertension and a cluster of lipid abnormalities known as atherogenic dyslipidemia.2,15 Although LDL-C levels are generally not strikingly elevated, this syndrome is characterized by the presence of atherogenic, small-dense LDL-particles, increased triglycerides levels, and low levels of HDL-C.5

Intensive efforts have focused on development of pharmacological strategies for treatment of this common lipid disorder. Therapeutic agents that target 3 distinct families of PPAR receptors (α, γ, and ∂) have been considered particularly promising.9,10,14 PPAR-α agonists primarily modulate lipid metabolism, lowering serum triglycerides levels and modestly increasing HDL-C levels. The fibric acid derivatives fenofibrate and gemfibrozil are relatively weak ligands for the PPAR-α receptor.3 The PPAR-γ agonists increase insulin sensitivity and are widely used as antidiabetic agents.10 PPAR-∂ agents are currently the subject of ongoing research.16

Greater understanding of the chemical structure and function of these nuclear receptors has enabled the pharmaceutical industry to develop increasingly potent and selective PPAR agonists. However, to date, no novel PPAR-α agent has reached an advanced stage of development. According to publicly accessible FDA documents, the pharmaceutical industry has filed at least 50 investigational new drug applications for new PPAR agonists.11 However, in nearly all cases, development was terminated due to toxicity.11 In 1 report, an FDA safety official described the organ systems involved in toxicity as “cardiac, skeletal muscle, renal, and bone marrow.”11 According to FDA officials, 2 dual α-γ agonists were discontinued due to elevations in serum creatinine levels, and rhabdomyolysis occurred in early-stage trials of a single α and another dual α-γ agonist.11 Five dual agonists were discontinued for “multi-species, multi-sex, multi-site increases in tumors with no safety margins for clinical exposures.”11 Another dual α-γ agonist, muraglitazar, was discontinued after publication of a report that this agent increased adverse cardiovascular outcomes.17 With the exception of muraglitazar, each of these drugs was discontinued without scientific publications describing their safety and efficacy.

In this study, we evaluated a potent and selective new PPAR-α agonist known as LY518674 in patients with atherogenic dyslipidemia or hypercholesterolemia. This report represents, to our knowledge, the first published description of the effects of a potent and selective PPAR-α agonist. Efficacy in an atherogenic dyslipidemia population was generally similar to that of fenofibrate, producing a 35% to 42% decrease in triglycerides levels and a 2% to 16% increase in HDL-C levels.

However, the LY518674 dose-response curves for Apo A-I and HDL-C were unusual, showing the greatest elevation in HDL-C levels (15.8%) at an intermediate dose of LY518674 (25μg) and almost no effect at the maximum tested dose of 100 μg. Since fenofibrate is known to affect both the production and catabolic rates of Apo AI, it is plausible that a potent PPAR-α agonist may have differential effects on these 2 processes at various doses, resulting in complex biphasic changes in HDL-C levels.18

In atherogenic dyslipidemia, there was a trend toward greater reduction of triglycerides levels with LY518674 at only the 50-μg dose, compared with fenofibrate (41.7% vs 32.8%, respectively; P = .08), but this dose did not result in an optimal increase in levels of HDL-C (11.1%). LY518674 had a unfavorable affect on LDL-C levels, increasing values significantly more than fenofibrate, 18.3% (50 μg) and 19.5% (100 μg) vs 2.3% for fenofibrate (P = .002 for both comparisons). In the hypercholesterolemia study, LY518674 (10 μg or 50 μg), when added to atorvastatin, produced no significant additional reductions in LDL-C levels, increased HDL-C levels by 0.6% to 11.9%, and decreased triglycerides levels an additional 20.4% to 42.7% (Table 4).

We also performed a post hoc analysis to explore the increase in LDL-C levels observed with LY518674 in the atherogenic dyslipidemia study but not in the hypercholesterolemia study. The increase in LDL-C levels with LY518674 showed a positive correlation with baseline levels of triglycerides (Figure 3). Accordingly, in the atherogenic dyslipidemia study, in which triglycerides levels were elevated at baseline, LDL-C levels increased in response to LY518674 therapy. In contrast, in the hypercholesterolemia study, in which triglycerides levels were less elevated, LY518674 moderately reduced levels of LDL-C.

Figure 3. Post Hoc Analysis of Relationship Between Levels of Triglycerides and Low-Density Lipoprotein Cholesterol (LDL-C)
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Formula for trend line = −28.13148 + 0.177(baseline triglycerides level) − 0.00009538(square of baseline triglycerides level). To convert triglycerides values to mmol/L, multiply by 0.0113.

In general, both fenofibrate and LY518674 were well tolerated, but some safety concerns emerged during treatment. In the dyslipidemia study, administration either of LY518674 at higher doses or of fenofibrate increased the AUC/t in levels of serum creatinine (P≤.001 compared with placebo). In some patients, serum creatinine levels increased above the upper limit of normal (38% in the fenofibrate treatment group and a maximum of 37.3% in the LY518674 treatment group [100-μg group in the dyslipidemia study]). Fenofibrate, but not LY518674, increased the AUC/t in levels of creatine phosphokinase (P = .004). However, no patients experienced rhabdomyolysis or acute renal failure. Elevation of serum creatinine has been reported with fenofibrate previously, although the etiology is controversial.1922 One report in 3 renal transplant patients demonstrated reversible allograft dysfunction with biopsy evidence of tubular toxicity.22 However, another study reported that increased metabolic production of creatinine, rather than renal dysfunction, contributed to the increase in serum creatinine levels.20 Although fenofibrate increased levels of creatine phosphokinase in our study, this agent has only rarely caused rhabdomyolysis in the absence of concomitant statin administration.23

The effects of LY518674 on lipoproteins raise some additional concerns. The dose-dependent increases in LDL-C levels when LY518674 was administered as monotherapy are clearly undesirable. LY518674 also produced substantial, dose-dependent increases in levels of Apo A-II, ranging up to 30% for the highest LY518674 dose (100 μg). While increases in Apo A-I levels are usually linked to clinical benefit, the impact of increases in Apo A-II levels is more controversial.2427 Some studies show protection from atherosclerosis, whereas others have linked increases in Apo A-II levels to adverse cardiovascular outcomes.24,25 Some reports have suggested that the higher the ratio of Apo A-II to Apo A-I, the greater the risk of adverse vascular events.26 The precise impact of altering the relative proportion of Apo A-II to Apo A-I on the functionality of HDL-C remains to be determined.

These findings have implications for the interpretation of clinical trials that have investigated the efficacy of fibrates.6,7,2830 Although gemfibrozil has been associated with improved cardiovascular outcomes in 2 randomized controlled trials, results of outcomes studies with other fibrates have been inconsistent. Bezafibrate, although not available in the United States, produced no benefit on clinical outcomes.29 A post hoc analysis suggested clinical benefit in patients with hypertriglyceridemia at baseline. A recent large study of fenofibrate in patients with diabetes showed no significant reduction in morbidity and a trend toward increased all-cause mortality.30 Whether this potential increase in mortality is derived from compound-specific toxicity of fenofibrate or is an adverse effect of PPAR-α activation remains uncertain. The short-term nature of our study (ie, 12 weeks of therapy in both trials) and the lack of data on clinical events during that period limit our ability to help clarify this issue. Accordingly, the net clinical benefit of existing and novel PPAR-α agonists remains to be determined.31,32

The results of this pair of trials demonstrate the challenges in developing new PPAR agonists as therapeutic agents. These drugs modulate activity of a large number of genes, some of which produce unknown effects. Accordingly, the beneficial effects of PPAR activation appear to be associated with a variety of untoward effects, which may include oncogenesis, renal dysfunction, rhabdomyolysis, and cardiovascular toxicity. Recently, the FDA began requiring 2-year preclinical oncogenicity studies for all PPAR-modulating agents prior to exposure of patients for durations longer than 6 months.11 Progress toward understanding these issues has been hampered by the absence of published reports of the benefits and hazards of novel agents. The promise of PPAR agonists stems primarily from the hope that more active agonists would produce more robust benefits. However, the current pair of studies do not support this hypothesis. Despite a potency approximately 10 000 times greater than fenofibrate and greater selectivity, LY518674 did not produce more favorable effects on lipoproteins compared with fenofibrate.

These findings underscore the importance of prompt and thorough reporting of clinical trials of novel pharmaceutical agents. Such studies advance the understanding of risks and benefits of new approaches and enable subsequent development programs to refine future study designs. Prompt publication also allows better protection of patient safety by providing study sponsors, investigators, and data and safety monitoring committees with a better appreciation of any potential risks that may require close monitoring.

Corresponding Author: Steven E. Nissen, MD, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195 (nissens@ccf.org).

Published Online: March 25, 2007 (doi:10.1001/jama.297.12.1362).

Author Contributions: Dr Nissen and the Cleveland Clinic Cardiovascular Coordinating Center had full and independent access to all of the data in the study, and Dr Nissen takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Nissen, Howey, Wang, Gomez.

Acquisition of data: Nissen, Howey, McErlean, Wang, Gomez, Russo.

Analysis and interpretation of data: Nissen, Nicholls, Wolski, Howey, Wang, Gomez.

Drafting of the manuscript: Nissen, Nicholls, Wang.

Critical revision of the manuscript for important intellectual content: Nissen, Nicholls, Wolski, Howey, McErlean, Gomez, Russo.

Statistical analysis: Nicholls, Wolski, Howey, Wang, Gomez.

Obtained funding: Nissen.

Administrative, technical, or material support: Nissen, Howey, McErlean.

Study supervision: Nissen, Howey, Russo.

Financial Disclosures: Dr Nissen reports having received research support from AstraZeneca, Eli Lilly, Pfizer, Sanofi-Aventis, Sankyo, and Takeda through the Cleveland Clinic Cardiovascular Coordinating Center. He also reports consulting for many pharmaceutical companies but requiring them to donate all honoraria and speaking fees directly to charity so that he does not receive income or a tax deduction. Dr Nicholls reports having received honoraria for lecturing from AstraZeneca, Merck Schering-Plough, and Pfizer, consulting fees from Anthera Pharmaceuticals and AstraZeneca, and research support from LipidSciences. Drs Howey, Wang, and Ms Gomez are employees of Eli Lilly. No other financial disclosures were reported.

Data and Safety Monitoring Board: James H. Stein, MD, University of Wisconsin, Madison (Chair); Kerry Lee, PhD, Duke Clinical Research Institute; Paul D. Thompson, MD, Hartford Hospital, Hartford, Conn; Christie M. Ballantyne, MD, Baylor College of Medicine, Houston, Tex; William Weintraub, MD, Emory Center for Outcomes Research, Atlanta, Ga; Robert L. Frye, Mayo Clinic, Rochester, Minn; and David Waters, MD, San Francisco General Hospital, San Francisco, Calif.

Investigators: Neem Research Group, Columbia, SC (James Allison, MD); Regional Physicians Research, High Point, NC (Gordon Arnold, MD); Cardiology Associates of North Mississippi, Tupelo (Barry Bertolet, MD); McLaren Regional Medical Center, Flint, Mich (David Brill, MD); Hillcrest Clinical Research, Simpsonville, SC (Robert Broker, MD); Altru Health Systems Hospital, Grand Forks, ND (James Brosseau, MD); Pulmonary & Research Associates, Spokane, Wash (Timothy Bruya, MD); Geisinger Clinc, Danville, Pa (Richard Butcher, MD); New West Physicians Clinical Research, Golden, Colo (Kenneth Cohen, MD); Wenatchee Valley Medical Center, Wenatchee, Wash (Steven Kaster, MD); South Denver Cardiology Associates, Littleton, Colo (J. Kern Buckner, MD); Dairyland Medical Center, Red Lion, Pa (Drake DeHart, DO); Scripps Clinic Rancho Bernardo, San Diego, Calif (Margaret Drehobl, MD); Radiant Research, Greer, SC (William Ellison, MD); Village Family Practice, Houston, Tex (Harold Fields, MD); Great Lakes Medical Research, Westfield, NY (Mark Hagen, MD); Research Institute of Middle America, Jeffersonville, Ind (D. Marty Denny, MD); Clinical Research Consultants, Hoover, Ala (Carol Johnson, MD); Health Trends Research, Baltimore, Md (Boris Kerzner, MD); Bend Memorial Clinic, Bend, Ore (Matthew Lasala, MD); Progressive Clinical Research, Vista, Calif (Jon LeLevier, MD); PAB Clinical Research, Brandon, Fla (Daniel Lorch, MD); Holston Medical Group, Kingsport, Tenn (Jerry Miller, MD); Morelli Family Practice, Stoneboro, Pa (Joseph Morelli, MD); Wichita Clinic, Wichita, Kan (Roberta Loeffler, MD); Crystal Lake Health Center, Benzonia, Mich (Richard Nielsen, MD); Rockville Internal Medicine Group, Rockville, Md (Alan Pollack, MD); Ranch View Family Medicine, Highlands Ranch, Colo (Gary Post, MD); Center for Clinical Research, Lexington, Ky (Neil Farris, MD); Cleveland Clinic, Cleveland, Ohio (Michael Rocco, MD); PharmaQuest, Greensboro, NC (John Russo, MD); Internal Medicine Research, Portland, Ore (W. Michael Ryan, MD); Holston Medical Group, Bristol, Tenn (James Schrenker, MD); CMVS Research Institute, Jupiter, Fla (Michael Stein, MD); St Joseph's Medical Center, Stockton, Calif (Shaukat Shah, MD); North Central Research, Mansfield, Ohio (David Subich, MD); Genesis Research International, Longwood, Fla (Raul Tamayo, MD); Iowa Heart Center, West Des Moines (William Wickemeyer, MD); Maine Research Associates, Auburn (Robert Weiss, MD); Founders Medical Practice, Philadelphia, Pa (Gary Yeoman, DO); Cardiology Research Associates, Boca Raton, Fla (David Mishkel, MD); Alpha Medical Research, Oviedo, Fla (Neil Patterson, MD); Medical Arts Research Collaborative, Excelsior Springs, Mo (James LaSalle, MD); University of Kansas Medical Center, Kansas City (Charles Porter, MD); Neem Research Group, Charlotte, NC (William Long, MD); Fayetteville Diagnostic Clinic, Fayetteville, Ark (James Salmon, MD); Great Lakes Family Care, Cadillac, Mich (William George, MD); Southgate Medical Group, West Seneca, NY (Brian Snyder, MD); Crystal Lake Health Center, Interlochen, Mich (Mark Barber, DO); Metrolina Medical Research, Charlotte, NC (George Read, MD); FPA Clinical Research, Kissimmee, Fla (Christopher Chappel, MD); Tricities Medical Research, Bristol, Tenn (David Morin, MD); New Hanover Medical Research, Wilmington, NC (Robert Hutchins, MD); Cedar-Crosse Research Center, Chicago, Ill (Danny Sugimoto, MD); Radiant Research, Philadelphia, Pa (Barry Packman, MD); Redrock Research Center, Las Vegas, Nev (Rachakonda Prabhu, MD); Neem Research Group of Raleigh, Raleigh, NC (John Yacono, MD); New Hope Research of Oregon, Portland (Patrick Rask, MD); and Piedmont Medical Research, Winston-Salem, NC (Stephen Bissette, MD). Each investigator was paid according to the study site agreement, with specific per-patient reimbursement milestones based on work performed. Payment was provided by the Cleveland Clinic Department of Finance and Contracts, under contract to the study sponsor (Eli Lilly and Co).

Funding/Support: This study was funded by Eli Lilly and Co.

Role of the Sponsor: Eli Lilly and Co participated actively in designing the study, developing the protocol, and provided logistical support during the trial. Monitoring of the study was performed by a contract research organization, Omnicare, under contract with the sponsor. The sponsor maintained the trial database. Primary statistical analysis was performed by statisticians employed by Eli Lilly. The manuscript was prepared by Dr Nissen and modified after consultation with the coauthors. The sponsor was permitted to review the manuscript and suggest changes, but the final decision on content was exclusively retained by the academic authors.

Independent Statistical Analysis: After completion of the trial, as specified in the study contract, a complete copy of the database was transferred to the Cleveland Clinic Cardiovascular Coordinating Center. An independent statistician, Kathy Wolski, MPH, received the entire raw data set, reviewed the analytic plan for appropriateness and accuracy, and independently confirmed all of the analyses prior to inclusion in the manuscript. All discrepancies in results were successfully resolved through consultation between Ms Wolski and statisticians employed by the sponsor.

Acknowledgment: We thank Craig Balog, BS (statistical programmer, Cleveland Clinic Cardiovascular Coordinating Center), and Kendra Jones, MS (statistical programmer, Eli Lilly and Co), Denise Mason, RN, Debbie Davey, RN, and Claire Pothier, MPH (project management, Cleveland Clinic). None of the individuals acknowledged received special compensation for their contributions.

Sharvill DE. Hyperlipaemic xanthomatosis treated with clofibrate: “dry discoid eczema.”  Proc R Soc Med. 1964;57:44-45
PubMed
Grundy SM. Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance.  Clin Cornerstone. 2006;8:(suppl 1)  S21-S27
PubMed   |  Link to Article
Després JP, Lemieux I, Robins SJ. Role of fibric acid derivatives in the management of risk factors for coronary heart disease.  Drugs. 2004;64:2177-2198
PubMed   |  Link to Article
Dayspring T, Pokrywka G. Fibrate therapy in patients with metabolic syndrome and diabetes mellitus.  Curr Atheroscler Rep. 2006;8:356-364
PubMed   |  Link to Article
Gazi IF, Tsimihodimos V, Tselepis AD, Elisaf M, Mikhailidis DP. Clinical importance and therapeutic modulation of small dense low-density lipoprotein particles.  Expert Opin Biol Ther. 2007;7:53-72
PubMed   |  Link to Article
Frick MH, Elo O, Haapa K.  et al.  Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease.  N Engl J Med. 1987;317:1237-1245
PubMed   |  Link to Article
Rubins HB, Robins SJ, Collins D.  et al.  Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.  N Engl J Med. 1999;341:410-418
PubMed   |  Link to Article
Vu-Dac N, Schoonjans K, Kosykh V.  et al.  Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor.  J Clin Invest. 1995;96:741-750
PubMed   |  Link to Article
Staels B, Fruchart JC. Therapeutic roles of peroxisome proliferator-activated receptor agonists.  Diabetes. 2005;54:2460-2470
PubMed   |  Link to Article
Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors.  Lancet. 1999;354:141-148
PubMed   |  Link to Article
El-Hage J.Center for Drug Evaluation and Research, US Food and Drug Administration.  Peroxisome proliferator-activated receptor (PPAR) antagonists: preclinical and clinical cardiac safety considerations. http://www.fda.gov/cder/present/DIA2006/El-Hage_CardiacSafety.ppt. Accessibility verified February 27, 2007
Xu Y, Mayhugh D, Saeed A.  et al.  Design and synthesis of a potent and selective triazolone-based peroxisome proliferator-activated receptor alpha agonist.  J Med Chem. 2003;46:5121-5124
PubMed   |  Link to Article
Singh JP, Kauffman R, Bensch W.  et al.  Identification of a novel selective peroxisome proliferator-activated receptor alpha agonist, 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2, 4-triazol-3-yl]propyl}phenoxy)propanoic acid (LY518674), that produces marked changes in serum lipids and apolipoprotein A-1 expression.  Mol Pharmacol. 2005;68:763-768
PubMed
National Cholesterol Education Program (NCEP) Expert Panel on Detection.  Evaluation, and Treatment of High Blood Cholesterol in Adults. 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.  JAMA. 2001;285:2486-2497
PubMed   |  Link to Article
Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction.  J Am Coll Cardiol. 2005;46:1225-1228
PubMed   |  Link to Article
Seimandi M, Lemaire G, Pillon A.  et al.  Differential responses of PPARalpha, PPARdelta, and PPARgamma reporter cell lines to selective PPAR synthetic ligands.  Anal Biochem. 2005;344:8-15
PubMed   |  Link to Article
Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus [published online ahead of print October 20, 2005].  JAMA. 2005;294:2581-2586
PubMeddoi:10.1001/jama.294.20   |  Link to Article
Watts GF, Barrett PH, Ji J.  et al.  Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome.  Diabetes. 2003;52:803-811
PubMed   |  Link to Article
Angeles C, Lane BP, Miller F, Nord EP. Fenofibrate-associated reversible acute allograft dysfunction in 3 renal transplant recipients: biopsy evidence of tubular toxicity.  Am J Kidney Dis. 2004;44:543-550
PubMed
Hottelart C, El Esper N, Rose F, Achard JM, Fournier A. Fenofibrate increases creatininemia by increasing metabolic production of creatinine.  Nephron. 2002;92:536-541
PubMed   |  Link to Article
Lipscombe J, Lewis GF, Cattran D, Bargman JM. Deterioration in renal function associated with fibrate therapy.  Clin Nephrol. 2001;55:39-44
PubMed
Broeders N, Knoop C, Antoine M, Tielemans C, Abramowicz D. Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only innocuous agent?  Nephrol Dial Transplant. 2000;15:1993-1999
PubMed   |  Link to Article
Barker BJ, Goodenough RR, Falko JM. Fenofibrate monotherapy induced rhabdomyolysis.  Diabetes Care. 2003;26:2482-2483
PubMed   |  Link to Article
Escolà-Gil JC, Marzal-Casacuberta A, Julve-Gil J.  et al.  Human apolipoprotein A-II is a pro-atherogenic molecule when it is expressed in transgenic mice at a level similar to that in humans: evidence of a potentially relevant species-specific interaction with diet.  J Lipid Res. 1998;39:457-462
PubMed
Castellani LW, Navab M, Van Lenten BJ.  et al.  Overexpression of apolipoprotein AII in transgenic mice converts high density lipoproteins to proinflammatory particles.  J Clin Invest. 1997;100:464-474
PubMed   |  Link to Article
Schultz JR, Verstuyft JG, Gong EL, Nichols AV, Rubin EM. Protein composition determines the anti-atherogenic properties of HDL in transgenic mice.  Nature. 1993;365:762-764
PubMed   |  Link to Article
Tailleux A, Duriez P, Fruchart JC, Clavey V. Apolipoprotein A-II, HDL metabolism and atherosclerosis.  Atherosclerosis. 2002;164:1-13
PubMed   |  Link to Article
 Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study.  Lancet. 2001;357:905-910
PubMed   |  Link to Article
 Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study.  Circulation. 2000;102:21-27
PubMed   |  Link to Article
Keech A, Simes RJ, Barter P.  et al. FIELD Study Investigators.  Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.  Lancet. 2005;366:1849-1861[published correction appears in Lancet. 2006;368:1420].
PubMed   |  Link to Article
Sambandam N, Morabito D, Wagg C, Finck BN, Kelly DP, Lopaschuk GD. Chronic activation of PPAR{alpha} is detrimental to cardiac recovery following ischemia [article posted online ahead of print September 9, 2005].  Am J Physiol Heart Circ Physioldoi:10.1152/ajpheart.00285.2005
Molavi B, Rasouli N, Mehta JL. Peroxisome proliferator-activated receptor ligands as antiatherogenic agents: panacea or another Pandora's box?  J Cardiovasc Pharmacol Ther. 2002;7:1-8
PubMed   |  Link to Article

Figures

Figure 1. Disposition of Patients in the Atherogenic Dyslipidemia Study
Graphic Jump Location
Figure 2. Disposition of Patients in the Hypercholesterolemia Study
Graphic Jump Location
Figure 3. Post Hoc Analysis of Relationship Between Levels of Triglycerides and Low-Density Lipoprotein Cholesterol (LDL-C)
Graphic Jump Location

Formula for trend line = −28.13148 + 0.177(baseline triglycerides level) − 0.00009538(square of baseline triglycerides level). To convert triglycerides values to mmol/L, multiply by 0.0113.

Tables

Table Graphic Jump LocationTable 1. Baseline Demographic Characteristics and Biochemical Parameters (Safety Population)
Table Graphic Jump LocationTable 2. Atherogenic Dyslipidemia Study: Absolute and Percentage Changes in Laboratory Parameters and Blood Pressure From Baseline Until Follow-up Visit
Table Graphic Jump LocationTable 3. Hypercholesterolemia Study: Absolute and Percentage Changes in Laboratory Parameters and Blood Pressure From Baseline Until Final Follow-up Visit
Table Graphic Jump LocationTable 4. Hypercholesterolemia Study: Additional Effects of LY518674 After Randomization to Atorvastatin (Percentage Change From 4 Weeks to End of Treatment)
Table Graphic Jump LocationTable 5. Atherogenic Dyslipidemia Study: Laboratory Safety Parameters*
Table Graphic Jump LocationTable 6. Hypercholesterolemia Study: Laboratory Safety Parameters*

References

Sharvill DE. Hyperlipaemic xanthomatosis treated with clofibrate: “dry discoid eczema.”  Proc R Soc Med. 1964;57:44-45
PubMed
Grundy SM. Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance.  Clin Cornerstone. 2006;8:(suppl 1)  S21-S27
PubMed   |  Link to Article
Després JP, Lemieux I, Robins SJ. Role of fibric acid derivatives in the management of risk factors for coronary heart disease.  Drugs. 2004;64:2177-2198
PubMed   |  Link to Article
Dayspring T, Pokrywka G. Fibrate therapy in patients with metabolic syndrome and diabetes mellitus.  Curr Atheroscler Rep. 2006;8:356-364
PubMed   |  Link to Article
Gazi IF, Tsimihodimos V, Tselepis AD, Elisaf M, Mikhailidis DP. Clinical importance and therapeutic modulation of small dense low-density lipoprotein particles.  Expert Opin Biol Ther. 2007;7:53-72
PubMed   |  Link to Article
Frick MH, Elo O, Haapa K.  et al.  Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease.  N Engl J Med. 1987;317:1237-1245
PubMed   |  Link to Article
Rubins HB, Robins SJ, Collins D.  et al.  Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.  N Engl J Med. 1999;341:410-418
PubMed   |  Link to Article
Vu-Dac N, Schoonjans K, Kosykh V.  et al.  Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor.  J Clin Invest. 1995;96:741-750
PubMed   |  Link to Article
Staels B, Fruchart JC. Therapeutic roles of peroxisome proliferator-activated receptor agonists.  Diabetes. 2005;54:2460-2470
PubMed   |  Link to Article
Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors.  Lancet. 1999;354:141-148
PubMed   |  Link to Article
El-Hage J.Center for Drug Evaluation and Research, US Food and Drug Administration.  Peroxisome proliferator-activated receptor (PPAR) antagonists: preclinical and clinical cardiac safety considerations. http://www.fda.gov/cder/present/DIA2006/El-Hage_CardiacSafety.ppt. Accessibility verified February 27, 2007
Xu Y, Mayhugh D, Saeed A.  et al.  Design and synthesis of a potent and selective triazolone-based peroxisome proliferator-activated receptor alpha agonist.  J Med Chem. 2003;46:5121-5124
PubMed   |  Link to Article
Singh JP, Kauffman R, Bensch W.  et al.  Identification of a novel selective peroxisome proliferator-activated receptor alpha agonist, 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2, 4-triazol-3-yl]propyl}phenoxy)propanoic acid (LY518674), that produces marked changes in serum lipids and apolipoprotein A-1 expression.  Mol Pharmacol. 2005;68:763-768
PubMed
National Cholesterol Education Program (NCEP) Expert Panel on Detection.  Evaluation, and Treatment of High Blood Cholesterol in Adults. 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.  JAMA. 2001;285:2486-2497
PubMed   |  Link to Article
Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction.  J Am Coll Cardiol. 2005;46:1225-1228
PubMed   |  Link to Article
Seimandi M, Lemaire G, Pillon A.  et al.  Differential responses of PPARalpha, PPARdelta, and PPARgamma reporter cell lines to selective PPAR synthetic ligands.  Anal Biochem. 2005;344:8-15
PubMed   |  Link to Article
Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus [published online ahead of print October 20, 2005].  JAMA. 2005;294:2581-2586
PubMeddoi:10.1001/jama.294.20   |  Link to Article
Watts GF, Barrett PH, Ji J.  et al.  Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome.  Diabetes. 2003;52:803-811
PubMed   |  Link to Article
Angeles C, Lane BP, Miller F, Nord EP. Fenofibrate-associated reversible acute allograft dysfunction in 3 renal transplant recipients: biopsy evidence of tubular toxicity.  Am J Kidney Dis. 2004;44:543-550
PubMed
Hottelart C, El Esper N, Rose F, Achard JM, Fournier A. Fenofibrate increases creatininemia by increasing metabolic production of creatinine.  Nephron. 2002;92:536-541
PubMed   |  Link to Article
Lipscombe J, Lewis GF, Cattran D, Bargman JM. Deterioration in renal function associated with fibrate therapy.  Clin Nephrol. 2001;55:39-44
PubMed
Broeders N, Knoop C, Antoine M, Tielemans C, Abramowicz D. Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only innocuous agent?  Nephrol Dial Transplant. 2000;15:1993-1999
PubMed   |  Link to Article
Barker BJ, Goodenough RR, Falko JM. Fenofibrate monotherapy induced rhabdomyolysis.  Diabetes Care. 2003;26:2482-2483
PubMed   |  Link to Article
Escolà-Gil JC, Marzal-Casacuberta A, Julve-Gil J.  et al.  Human apolipoprotein A-II is a pro-atherogenic molecule when it is expressed in transgenic mice at a level similar to that in humans: evidence of a potentially relevant species-specific interaction with diet.  J Lipid Res. 1998;39:457-462
PubMed
Castellani LW, Navab M, Van Lenten BJ.  et al.  Overexpression of apolipoprotein AII in transgenic mice converts high density lipoproteins to proinflammatory particles.  J Clin Invest. 1997;100:464-474
PubMed   |  Link to Article
Schultz JR, Verstuyft JG, Gong EL, Nichols AV, Rubin EM. Protein composition determines the anti-atherogenic properties of HDL in transgenic mice.  Nature. 1993;365:762-764
PubMed   |  Link to Article
Tailleux A, Duriez P, Fruchart JC, Clavey V. Apolipoprotein A-II, HDL metabolism and atherosclerosis.  Atherosclerosis. 2002;164:1-13
PubMed   |  Link to Article
 Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study.  Lancet. 2001;357:905-910
PubMed   |  Link to Article
 Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study.  Circulation. 2000;102:21-27
PubMed   |  Link to Article
Keech A, Simes RJ, Barter P.  et al. FIELD Study Investigators.  Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.  Lancet. 2005;366:1849-1861[published correction appears in Lancet. 2006;368:1420].
PubMed   |  Link to Article
Sambandam N, Morabito D, Wagg C, Finck BN, Kelly DP, Lopaschuk GD. Chronic activation of PPAR{alpha} is detrimental to cardiac recovery following ischemia [article posted online ahead of print September 9, 2005].  Am J Physiol Heart Circ Physioldoi:10.1152/ajpheart.00285.2005
Molavi B, Rasouli N, Mehta JL. Peroxisome proliferator-activated receptor ligands as antiatherogenic agents: panacea or another Pandora's box?  J Cardiovasc Pharmacol Ther. 2002;7:1-8
PubMed   |  Link to Article

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