Choline Fenofibrate Research Articles

Dyslipidemia Correction by Combination of Statin and Choline Fenofibrate in Diabetic Patients with Multifocal Atherosclerosis

Dyslipidemia Correction by Combination of Statin and Choline Fenofibrate in Diabetic Patients with Multifocal Atherosclerosis

Efficacy and Safety of Fenofibrate-Statin Combination Therapy in Patients With Inadequately Controlled Triglyceride Levels Despite Previous Statin Monotherapy: A Multicenter, Randomized, Double-blind, Phase IV Study

PurposeResidual cardiovascular risk reduction by fenofibrate in patients with high serum triglyceride (TG) levels despite previous statin monotherapy is not well characterized. The purpose of this study was to evaluate the efficacy and safety of a combination of choline fenofibrate and statin in patients with inadequately controlled TG levels despite previous statin monotherapy. MethodsThis prospective, multicenter, randomized, double-blind study was conducted in Korea. A total of 133 patients with controlled LDL-C but elevated TG levels, already receiving statin monotherapy, were enrolled in the study, which was conducted from July 2018 to December 2019. Patients were randomly assigned to receive combination therapy with choline fenofibrate and statin or statin monotherapy in a 1:1 ratio. After 8 weeks of treatment, the lipid profiles and safety parameters of the patients in the 2 groups were compared. FindingsThe study included 127 patients (64 in the combination group and 63 in the control group) older than 19 years. After 8 weeks of therapy, mean serum TG levels significantly decreased from 269.8 to 145.5 mg/dL (P < 0.0001) in the combination therapy group, whereas no significant changes occurred in the statin monotherapy group (from 271.1 to 280.5 mg/dL). Contrarily, the mean serum HDLC levels significantly increased from 45.0 to 50.4 mg/dL (P = 0.0004) in the combination therapy group, whereas there were no significant changes in the monotherapy group (from 44.3 to 44.7 mg/dL). There were no additional serious adverse events in the combination therapy group compared with the statin monotherapy group. ImplicationsThe combination therapy using choline fenofibrate and statin was found to be effective in serum TG control and likely tolerable in patients with high TG levels despite statin monotherapy. A larger study, conducted for a longer duration, is needed to evaluate the effectiveness of this combination in reducing cardiovascular risk. ClinicalTrials.gov identifier: NCT03874260.

Effects of acute glial cell activation on memory performance – Implications for treatment of cognitive symptoms in neurological and psychiatric disorders

Paclitaxel, a widely used anti-cancer drug, is frequently associated with prolonged and severe peripheral neuropathies (PIPN), associated with neuroinflammation. Currently, PIPN effective treatments are lacking. Peroxisome Proliferator-Activated Receptor-α (PPAR-⍺) can modulate inflammatory responses. Thus, the use of PPAR-⍺ agonists, such as fibrates (fenofibrate and choline-fenofibrate), currently used in dyslipidemia treatment, could represent an interesting therapeutic approach in PIPN.Our studies tested the efficacy of fenofibrate (150 mg/kg, daily, i.p.) and choline fenofibrate (60 mg/kg daily, p.o.) in reversing and preventing the development of PIPN (paclitaxel: 8 mg/kg, i.p., every other day for 4 days) in male and female C57BL/6J mice. Mechanical and cold hypersensitivity, conditioned place preference, sensory nerve action potential (SNAP), as well as the expression of PPAR-⍺, TNF-⍺, IL-1β and IL-6 mRNA were evaluated.While fenofibrate treatment partially reversed and prevented the development of mechanical hypersensitivity, this was completely reversed and prevented by choline-fenofibrate. Both fibrates were able to completely reverse and prevent cold hypersensitivity induced by paclitaxel. The reduction of SNAP amplitude induced by paclitaxel was also reversed by both fenofibrate and choline-fenofibrate. Our results indicate that suppression of paclitaxel-induced hypersensitivity by fibrates involves the regulation of PPAR-⍺ expression and decrease neuroinflammation in DRG. Finally, the co-treatment of Paclitaxel and fenofibric acid (fibrates active metabolite) was tested on different cancer cell lines, no decrease in the antitumoral effect of paclitaxel was observed.Taken together, our results show for the first time the therapeutic potential (prevention and reversal) of fibrates in PIPN and opens to a potential pharmacological repurposing of these drugs.

Targeting Peroxisome Proliferator-Activated Receptor-α (PPAR- α) to reduce paclitaxel-induced peripheral neuropathy

Background and purposePaclitaxel, a widely used anti-cancer drug, is frequently associated with prolonged and severe peripheral neuropathies (PIPN), associated with neuroinflammation. Currently, PIPN effective treatments are lacking. Peroxisome Proliferator-Activated Receptor-α (PPAR-⍺) can modulate inflammatory responses. Thus, the use of PPAR-⍺ agonists, such as fibrates (fenofibrate and choline-fenofibrate), currently used in dyslipidemia treatment, could represent an interesting therapeutic approach in PIPN. Experimental approachOur studies tested the efficacy of fenofibrate (150 mg/kg, daily, i.p.) and choline fenofibrate (60 mg/kg daily, p.o.) in reversing and preventing the development of PIPN (paclitaxel: 8 mg/kg, i.p., every other day for 4 days) in male and female C57BL/6J mice. Mechanical and cold hypersensitivity, conditioned place preference, sensory nerve action potential (SNAP), as well as the expression of PPAR-⍺, TNF-⍺, IL-1β and IL-6 mRNA were evaluated. Key resultsWhile fenofibrate treatment partially reversed and prevented the development of mechanical hypersensitivity, this was completely reversed and prevented by choline-fenofibrate. Both fibrates were able to completely reverse and prevent cold hypersensitivity induced by paclitaxel. The reduction of SNAP amplitude induced by paclitaxel was also reversed by both fenofibrate and choline-fenofibrate. Our results indicate that suppression of paclitaxel-induced hypersensitivity by fibrates involves the regulation of PPAR-⍺ expression and decrease neuroinflammation in DRG. Finally, the co-treatment of Paclitaxel and fenofibric acid (fibrates active metabolite) was tested on different cancer cell lines, no decrease in the antitumoral effect of paclitaxel was observed. Conclusions and implicationsTaken together, our results show for the first time the therapeutic potential (prevention and reversal) of fibrates in PIPN and opens to a potential pharmacological repurposing of these drugs.

Abstract LB-097: Whole transcriptome dose response profiling enables characterization of efficacy, metabolism, side effects and cytotoxicity in a single comprehensive assay

Abstract Dose response assays are used throughout drug discovery and are key to comparing efficacy and safety, however, because of assay complexity and poor quantitative repeatability, gene expression-based dose response assays have not been successfully developed and adopted. Measuring dose response changes in cellular signaling pathways is challenging, as multiple pathways interact in a complex inter-connected manner. Benchmark dose (BMD) approaches allow researchers to quantitatively break down the complexity in an analyzable stepwise format for use in basic research, medicinal chemistry and toxicology. A BMD is calculated utilizing methods similar to an EC50 but does not differentiate between induction and suppression. By using this approach, it is possible to calculate a “convergent” BMD for each gene by fitting the data to a panel of kinetic models including Hill, Power, Exponential, and Linear. A software package, BMDExpress 2.0, has been developed by a consortium of EPA, NTP, Health Canada, and others, to facilitate the use of BMD calculations. The software can filter the data according to user defined parameters for the ~20,000 genes measured by the TempO-Seq® whole transcriptome targeted gene expression assay (Yeakley et al, PLOSone, 2017) which is an addition-only assay that uses crude cell lysates rather than extracted RNA. This enables high sample throughput from a minimal number of cells, carried out manually or with standard automation hardware in 96-well microplates, without the need of new equipment. The software determines a BMD value which can be a % change or change relative to SD, such as a BMD1SD. By tracking how individual genes respond to increasing doses, it is possible to differentiate between the onset of efficacy vs drug metabolism, side effects, and cytotoxicity. Simultaneously, it allows the identification of specific molecular pathways that are modulated by a given compound. We collected whole transcriptome dose response from Choline Fenofibrate treated HepG2 cells, computed the BMD1SD for each gene using BMDExpress, and generated accumulation plots that allowed monitoring of modulated genes and pathways in a dose-response manner. Genes and pathways associated with the known mechanistic efficacy of Fenofibrate were modulated at the lowest BMD1SD, followed by genes associated with its metabolism, and then by genes associated with side effects, then cytotoxicity at higher doses, indicated by a sudden, coordinated change in expression levels in a large number of genes. We carried out connectivity mapping to identify key molecular targets, by comparing BMD1SD values to the conventional mapping based on fold change. Our results demonstrate that high quality whole transcriptome dose response data generated by TempO-Seq® assay can be used to distinguish not only a therapeutic window of efficacy vs side effects but also factor in drug metabolism and cytotoxicity. Furthermore, gene expression BMD1SD analysis can identify novel target genes based on connectivity mapping. Citation Format: Megha Raghunathan, Elliot Imler, Christy Trejo, Peter Shepard, Bruce Seligmann. Whole transcriptome dose response profiling enables characterization of efficacy, metabolism, side effects and cytotoxicity in a single comprehensive assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-097.

Management of patient with famil ial combined hyperlipoproteinemia: a case study

Familial combined hyperlipoproteinemia is considered one of the most common genetic hyperlipidemias in the general population with estimated prevalence 0.5 %–2.0 % of all inherited dyslipidemias. This disorder frequently coexists with other metabolic diseases such as obesity, insulin resistance, hypertension, non-alcoholic fatty liver disease. Association of hyperlipoproteinemia and type 2 diabetes mellitus can be explained due to the fact, that familial combined hyperlipoproteinemia is caused by genetic variability, including genes encoding the upstream transcription factor 1. The last regulates nearly 40 genes implicated in lipid, lipoprotein and carbohydrate metabolism, as well as immune response. Polymorphism in the upstream transcription factor 1 is strongly associated with dyslipidemia, impaired glucose tolerance, insulin resistance, and type 2 diabetes mellitus. In this report on example of clinical case we want to pay attention of practitioners to the problem of familial causes of hyperlipidemias, which leads to early onset of atherosclerosis, cardiovascular disease, and, finally, to premature disability of the affected person. Because of the frequent overlapping with the features of metabolic syndrome, this serious disorder is often not recognized and treated timely. Our patient was a 43 year old male, who was referred to the clinic with complaints of angina pain and dyspnoea provoked by minimal physical exertion, palpitations, irregular heartbeats, lower extremities and face oedema. At the age of thirty in the patient have developed type 2 diabetes mellitus, during last 7 years it was insulin dependent, the course was severe, glycaemia was poorly controlled by the therapy. Also he had essential hypertension III grade. At the age of 37 years the patient suffered from ST-elevated myocardial infarction, one year later occurred recurrent myocardial infarction. His family history was strongly positive for atherosclerosis and cardiovascular disease, as well as type 2 diabetes mellitus. In laboratory testing the fasting blood sample revealed a grossly lipemic serum, with total cholesterol level 17.75 mmol/L, very low density lipoproteins 3.41 mmol/L, low density lipoproteins 13.64 mmol/L, high density lipoproteins 0.7 mmol/L. Diagnosis: «Familial combined hyperlipoproteinemia (Fredrickson type 2B). Acute coronary syndrome: Unstable angina IIB. Postinfarction (STEMI 2014, 2015) cardiosclerosis. Essential hypertension III degree III stage. Heart failure with left ventricular systolic and diastolic dysfunction, EF 36 %. III functional class NYHA. Stage D AHA. Risk score 4 (very high).Type 2 diabetes mellitus, insulin dependent, severe course. Non-alcoholic fatty liver, 2 degree. Nodular goitre I degree, euthyroid state» was established. Management of this patient includes lifestyle modification and combined lipid lowering therapy in high doses: rosuvastatin and choline fenofibrate. Unfortunately, in this case target levels of cholesterol and triglycerides were not achieved: minimal level of total cholesterol was 12.29 mmol/L, and level of triglycerides was 41.48 mmol/L. Risk estimates based on risk charts, scores, or functions used in the general population, probably grossly underestimate the real risk of this patient with familial combined hyperlipoproteinemia. Coexistence of extremely high level of cholesterol and type 2 diabetes mellitus significantly aggravates and advances each other's course, comparing with the isolated disorders.

Formulation and characterization of choline fenofibrate sustained release capsule

The drug ABT-335 (Fenofibricacid ) choline fenofibrate found to be useful in the treatment of dyslipidemia as compare with other fibrate. So the present investigation to developed mini-tablets to overcome the dose dumping problem by regular shape, uniformity, smooth surface excellent size and encapsulated in capsule to improve the efficacy and bioavailability of the drug. Different formulations were developed by utilizingcontrolling of the release rate and gel forming polymers like microcrystalline cellulose, hypromellose by dry granulation technique. Among all formulation SRM-3 having the drug release for longer period of time as compare to other formulation. SRM-3 was found to be stable during stability study for one month.&#x0D; Keywords: ABT-335 (Fenofibric acid) choline fenofibrate, like microcrystalline cellulose, hypromellose, sustained release matrix tablet.

Comparison of Efficacy and Safety of Fixed Dose Combination of Rosuvastatin and Choline Fenofibrate to Fixed Dose Combination of Rosuvastatin and Fenofibrate in Patients of Mixed Dyslipidemia: A Randomized, Open-label, Multicentre Clinical Trial in Indian Population.

Introduction:This study was conducted to evaluate the safety and efficacy of fixed-dose combination (FDC) of rosuvastatin and choline fenofibrate in comparison to rosuvastatin and fenofibrate FDC among Indian patients of mixed dyslipidemia. This would be a first study evaluating FDC of rosuvastatin and choline fenofibrate in Indian population.Methods:A multicenter, open-label, randomized, active controlled, comparative, parallel-design study was conducted at 12 centers spread all across India. Mixed dyslipidemic patients aged 18–70 years were randomized to FDC of rosuvastatin 10 mg and choline fenofibrate 135 mg (RCF group) and FDC of rosuvastatin 10 mg and fenofibrate 160 mg (RF group) once daily for approximately 180 days. The primary endpoint of study was percentage change in serum triglyceride level at the end of study from baseline.Results:Of 290 patients screened, 240 patients were enrolled in this study (120 patients in each group). At the end of 180 days, there was a significant reduction in triglyceride level in both the groups (−37.7% in RCF group and −37.8% reduction in RF group; P < 0.0001 for both); however, the difference between both the groups was not statistically significant (P = 0.94). Similarly, there was significant increase (P < 0.0001 for both) in high-density lipoprotein cholesterol (HDL-C) in both groups (+17.8% in RCF group and +14.9% in rosuvastatin fenofibrate RF group). Low-density lipoprotein cholesterol (LDL-C), very low-LDL (VLDL-C), and total cholesterol were also reduced significantly in both groups (P < 0.0001). However, the difference between two groups for increase in HDL-C and decrease in LDL-C, VLDL-C, and total cholesterol was not significant. Both the treatments were safe and well tolerated.Conclusion:Overall, FDC of rosuvastatin and choline fenofibrate is as safe and effective as rosuvastatin and fenofibrate combination in Indian patients with mixed dyslipidemia with added advantage improved patient compliance as it can be taken irrespective of intake of food.

Absolute oral bioavailability of fenofibric acid and choline fenofibrate in rats determined by ultra-performance liquid chromatography tandem mass spectrometry.

Choline fenofibrate is the choline salt of fenofibric acid, which releases free fenofibric acid in the gastrointestinal tract. To estimate the absolute oral bioavailability of fenofibric acid and choline fenofibrate, a novel and sensitive UPLC-MS/MS method with liquid-liquid extraction procedure was developed for the determination of fenofibric acid in rat plasma. The separation was achieved on a Phenomenex Kinetex C18 column (50 × 2.1 mm, 2.6 μm) containing 2 mm ammonium acetate-methanol with a gradient elution program. Validations of this method including specificity, sensitivity (limit of quantification, 5 ng/mL), linearity (0.005-10 μg/mL), accuracy (within ±4.3%), precision (intra- and inter-day coefficient of variation <11.3%), recovery (94.9-105.2% for fenofibric acid), matrix effect, stability and dilution, were all within acceptable limits. This method successfully supported the determination of fenofibric acid and choline fenofibrate. The absolute oral bioavailability was 93.4% for choline fenofibrate and 40.0% for fenofibric acid. These results suggested that choline fenofibrate and fenofibric acid had a better in vivo pharmacokinetic behavior than that of fenofibrate. The two new orally administrated pharmaceuticals, fenofibric acid and choline fenofibrate, can be developed as alternatives to fenofibrate.

Crystal structure of choline fenofibrate (Trilipix®), (C5H14NO) (C17H14ClO4)

The crystal structure of choline fenofibrate has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. Choline fenofibrate crystallizes in space groupPbca(#61) witha= 12.341 03(2),b= 28.568 70(6),c= 12.025 62(2) Å,V= 4239.84(1) Å3, andZ= 8. The hydroxyl group of the choline anion makes a strong hydrogen bond to the ionized carboxylate group of the fenofibrate anion. Together with C–H···O hydrogen bonds, these link the cations and anions into layers parallel to theac-plane. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™.

Effect of magnesium carbonate on the solubility, dissolution and oral bioavailability of fenofibric acid powder as an alkalising solubilizer.

To investigate the possibility of developing a novel oral pharmaceutical product using fenofibric acid instead of choline fenofibrate, the powder properties, solubility, dissolution and pharmacokinetics in rats of fenofibrate, choline fenofibrate and fenofibric acid were compared. Furthermore, the effect of magnesium carbonate, an alkalising agent on the solubility, dissolution and oral bioavailability of fenofibric acid was assessed, a mixture of fenofibric acid and magnesium carbonate being prepared by simple blending at a weight ratio of 2/1. The three fenofibrate derivatives showed different particle sizes and melting points with similar crystalline shape. Fenofibric acid had a significantly higher aqueous solubility and dissolution than fenofibrate, but significantly lower solubility and dissolution than choline fenofibrate. However, the fenofibric acid/magnesium carbonate mixture greatly improved the solubility and dissolution of fenofibric acid with an enhancement to levels similar with those for choline fenofibrate. Fenofibric acid gave lower plasma concentrations, AUC and Cmax values compared to choline fenofibrate in rats. However, the mixture resulted in plasma concentrations, AUC and Cmax values levels not significantly different from those for choline fenofibrate. Specifically, magnesium carbonate increased the aqueous solubility, dissolution and bioavailability of fenofibric acid by about 7.5-, 4- and 1.6-fold, respectively. Thus, the mixture of fenofibric acid and magnesium carbonate at the weight ratio of 2/1 might be a candidate for an oral pharmaceutical product with improved oral bioavailability.

Comparison of efficacy and safety of choline fenofibrate (fenofibric acid) to micronized fenofibrate in patients of mixed dyslipidemia: A randomized, open-label, multicenter clinical trial in Indian population.

Introduction:Choline fenofibrate is a newly developed choline salt of fenofibric acid, which is more hydrophilic than fenofibrate. This study was initiated to evaluate the safety and efficacy of choline fenofibrate in comparison to micronized fenofibrate among Indian patients of mixed dyslipidemia.Methods:A multicenter, open-label, randomized, active controlled, comparative, parallel group study was conducted at around 10 centers spread all across the country. Mixed dyslipidemia patients (serum triglycerides [TG] levels between 150 and 500 mg/dl), aged 18–70 years and taking stable statin dose for 8 weeks were randomized to choline fenofibrate 135 mg delayed release tablets and micronized fenofibrate 160 mg tablets once daily for 12 weeks. The primary endpoint of the study was percentage change in serum TG level at the end of 12 weeks.Results:A total of 226 patients were enrolled in this study, of which 116 patients were administered choline fenofibrate and 110 patients were administered micronized fenofibrate. At the end of 12 weeks, there was a significant reduction in TG level (34.24% in choline fenofibrate group and 38.13% reduction in micronized fenofibrate group). However, the difference between group was not statistically different (P = 0.471). Similarly, there was a significant increase in high-density lipoprotein cholesterol at the end of 12 weeks (10% increase in choline fenofibrate group and 9% increase in micronized fenofibrate group); but the difference between the group was not statistically significant (P = 0.598). Both the treatment was safe and well tolerated.Conclusion:Choline fenofibrate delayed release 135 mg is as safe and effective as 160 mg of micronized fenofibrate in Indian patients with mixed dyslipidemia.

Novel fenofibric acid-loaded controlled release pellet bioequivalent to choline fenofibrate-loaded commercial product in beagle dogs

The objective of this study was to develop a novel fenofibric acid-loaded controlled release pellet showing enhanced, or equivalent to, bioavailability compared with two commercially available products containing fenofibrate or choline fenofibrate. The effect of solubilizing agents on drug solubility and the impact of fillers on core properties were investigated. Among them, magnesium carbonate most improved drug solubility, and κ-carrageenan provided the best spherical cores. The fenofibric acid-loaded pellet was prepared with magnesium carbonate and κ-carrageenan employing the extrusion/spheronizing technique followed by coating with ethylcellulose. Furthermore, dissolution and pharmacokinetic study in beagle dogs were performed compared to the fenofibrate-loaded commercial tablet (FCT) and choline fenofibrate-loaded commercial mini-tablet (CFCM). This fenofibric acid-loaded pellet showed controlled release of the drug in phosphate buffer (pH 6.8) and 0.025M sodium laurylsulfate within 4h. Furthermore, this pellet and CFCM exhibited similar dissolution profiles. Plasma concentrations greater than 1000ng/ml were maintained from 30min to 8h, suggesting a sustained release pattern. Also, the fenofibric acid-loaded pellet gave significantly higher AUC and Cmax values than FCT, indicating that it improved the bioavailability of fenofibrate due to enhanced solubility and sustained release. In addition, this pellet and CFCM were not significantly different in terms of pharmacokinetic parameters including AUC, Cmax and Tmax. Thus, this pellet was bioequivalent to CFCM in beagle dogs. In conclusion, this fenofibric acid-loaded controlled release pellet would be a potential alternative to the choline fenofibrate-loaded commercial product.

Correction to Interesting Morphological Behavior of Organic Salt Choline Fenofibrate: Effect of Supersaturation and Polymeric Impurity

Correction to Interesting Morphological Behavior of Organic Salt Choline Fenofibrate: Effect of Supersaturation and Polymeric Impurity

Interesting Morphological Behavior of Organic Salt Choline Fenofibrate: Effect of Supersaturation and Polymeric Impurity

Crystal habit of drug molecules can have significant influence on the processing and performance of pharmaceutical products. During the development of Trilipix, a pharmaceutical product used for the treatment of mixed dyslipidemia, several crystal habits were observed for the active ingredient choline fenofibrate. The dissolution and performance of the drug product were not impacted by changes in crystal habit of the active ingredient due to high solubility of the drug. However, the formulation process was impacted by variations in crystal habit of the active ingredient, requiring robust control of the crystal habit. The crystal habit was greatly influenced by supersaturation during crystallization from a mixed solvent system comprising methanol and isopropanol. In addition to supersaturation, trace levels of a polymeric impurity in the starting material fenofibrate had a detrimental effect on the crystal habit. This article discusses the effects of these factors on the crystal habit of choline fenofibrate and the design of a crystallization process to deliver the target crystal habit, most suited to the formulation process. The article also provides preliminary mechanistic insights into the crystal habit of this organic salt using an extension of the spiral growth model for morphology prediction of organic molecular crystals. An attempt is made to explain the effect of supersaturation and impurity on the crystal habit of choline fenofibrate using the concepts of stability of surfaces, building units, periodic bond chain theory, and the spiral growth model.

Effects of fenofibric acid on carotid intima-media thickness in patients with mixed dyslipidemia on atorvastatin therapy: randomized, placebo-controlled study (FIRST).

To assess whether adding a fibrate to statin therapy reduces residual cardiovascular risk associated with elevated triglycerides and low high-density lipoprotein cholesterol, The Evaluation of Choline Fenofibrate (ABT-335) on Carotid Intima-Media Thickness (cIMT) in Subjects with Type IIb Dyslipidemia with Residual Risk in Addition to Atorvastatin Therapy (FIRST) trial evaluated the effects of fenofibric acid (FA) treatment on cIMT in patients with mixed dyslipidemia on atorvastatin. This multicenter, double-blind, placebo-controlled study was performed in patients with mixed dyslipidemia (fasting triglycerides, ≥150 mg/dL; high-density lipoprotein cholesterol, ≤45 [men] or 55 mg/dL [women]; low-density lipoprotein cholesterol, ≤100 mg/dL once and averaging ≤105 mg/dL) and a history of coronary heart disease or risk equivalent. Patients on background atorvastatin (continued on starting dose or titrated to 40 mg, if needed) were randomized to FA 135 mg or placebo. The primary end point was rate of change from baseline through week 104 of the mean posterior-wall cIMT, measured by ultrasound. In patients with controlled low-density lipoprotein cholesterol while on atorvastatin background therapy, rate of change in posterior-wall cIMT was similar with FA plus atorvastatin (-0.006 mm/y) versus atorvastatin monotherapy (0.000 mm/y; P=0.22). FA plus atorvastatin was favored (P<0.05) in 5 of 24 prespecified subgroups: age ≥60 years, history of coronary artery disease, cIMT >0.795 mm, triglycerides 170 to 235 mg/dL, and statin use at entry. Adverse events were consistent with the known safety profiles of both drugs; however, FA plus atorvastatin was associated with a greater incidence of renal-related adverse events compared with atorvastatin monotherapy (6.5% versus 0.9%). Compared with atorvastatin monotherapy, FA plus atorvastatin did not further decrease cIMT progression in high-risk patients with mixed dyslipidemia.

Study Design, Rationale, and Baseline Characteristics: Evaluation of Fenofibric Acid on Carotid Intima-Media Thickness in Patients with Type IIb Dyslipidemia with Residual Risk in Addition to Atorvastatin Therapy (FIRST) Trial

PurposeElevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels contribute to cardiovascular disease risk and can be effectively treated with fenofibric acid. A trial is under way to evaluate the effect of once-daily fenofibric acid or placebo on carotid intima-media thickness (CIMT) progression in patients with controlled low-density lipoprotein cholesterol (LDL-C) levels achieved through atorvastatin treatment, but with high TG and low HDL-C levels.MethodsIn this multicenter, double-blind study, 682 patients were randomized to once-daily delayed-release capsules of choline fenofibrate 135 mg (fenofibric acid [Trilipix®; Abbott, North Chicago, IL]) or placebo plus atorvastatin treatment after a 2- to 10-week diet and atorvastatin run-in period. Key inclusion criteria included age ≥45 years; posterior-wall common CIMT ≥0.7 mm on at least one side at baseline; fasting results of TG ≥150 mg/dL, and HDL-C ≤45 mg/dL for men or HDL-C ≤55 mg/dL for women at screening while receiving atorvastatin; controlled LDL-C; and known coronary heart disease (CHD) or a CHD risk equivalent. The primary efficacy variable is the rate of change from baseline through week 104 in the mean posterior-wall intima-media thickness of the common carotid arteries (composite value of left and right sides).ConclusionsThis trial is the first to examine the effect of fenofibric acid on CIMT and the first CIMT trial to select patients with controlled LDL-C and elevated TG and low HDL-C as inclusion criteria. Also, this trial will prospectively evaluate the effect of treatment on LDL particles and address shortcomings of previous CIMT trials.