Quasi-Classical Trajectory Calculation of Rate Constants Using an Ab Initio Trained Machine Learning Model (aML-MD) with Multifidelity Data.

Machine learning (ML) provides a great opportunity for the construction of models with improved accuracy in classical molecular dynamics (MD). However, the accuracy of a ML trained model is limited by the quality and quantity of the training data. Generating large sets of accurate ab initio training data can require significant computational resources. Furthermore, inconsistent or incompatible data with different accuracies obtained using different methods may lead to biased or unreliable ML models that do not accurately represent the underlying physics. Recently, transfer learning showed its potential for avoiding these problems as well as for improving the accuracy, efficiency, and generalization of ML models using multifidelity data. In this work, ab initio trained ML-based MD (aML-MD) models are developed through transfer learning using DFT and multireference data from multiple sources with varying accuracy within the Deep Potential MD framework. The accuracy of the force field is demonstrated by calculating rate constants for the H + HO2 → H2 + 3O2 reaction using quasi-classical trajectories. We show that the aML-MD model with transfer learning can accurately predict the rate constants while reducing the computational cost by more than five times compared to the use of more expensive quantum chemistry training data sets. Hence, the aML-MD model with transfer learning shows great potential in using multifidelity data to reduce the computational cost involved in generating the training set for these potentials.

Modelling the effect of surface charging on plasma synthesis of ammonia using DFT.

Non-equilibrium plasma has been found to have a synergistic effect on catalytic synthesis of NH3. The non-equilibrium plasma and catalyst surface together could affect NH3 synthesis through several mechanisms. Charging of the catalyst surface in the presence of non-equilibrium plasma is one such mechanism. We employed density functional theory (DFT) calculations to understand the effect of surface charge on surface reactivity of γ-Al2O3 supported single metal atom catalysts and a metal cluster. We investigated the effect of surface charge on adsorption energies of common adsorbates involved in NH3 synthesis. It is found that adsorption energy of N, N2, H, H2, NH and NH2 on metal atoms increases by up to ∼1.2 eV, whereas NH3 desorption is increased by up to 0.45 eV upon surface charging. The present results provide a new mechanism of plasma enhanced catalysis potentially explaining why Ni, Pt and Co have better catalytic performance compared to Ru and Fe in ammonia plasma catalysis. Furthermore, we found that the correlations between adsorption energies of adsorbates change significantly with surface charging. These findings suggest that surface charging might play an important role in plasma synthesis of NH3.

A stable atmospheric-pressure plasma for extreme-temperature synthesis.

Plasmas can generate ultra-high-temperature reactive environments that can be used for the synthesis and processing of a wide range of materials1,2. However, the limited volume, instability and non-uniformity of plasmas have made it challenging to scalably manufacture bulk, high-temperature materials3-8. Here we present a plasma set-up consisting of a pair of carbon-fibre-tip-enhanced electrodes that enable the generation of a uniform, ultra-high temperature and stable plasma (up to 8,000 K) at atmospheric pressure using a combination of vertically oriented long and short carbon fibres. The long carbon fibres initiate the plasma by micro-spark discharge at a low breakdown voltage, whereas the short carbon fibres coalesce the discharge into a volumetric and stable ultra-high-temperature plasma. As a proof of concept, we used this process to synthesize various extreme materials in seconds, including ultra-high-temperature ceramics (for example, hafnium carbonitride) and refractory metal alloys. Moreover, the carbon-fibre electrodes are highly flexible and can be shaped for various syntheses. This simple and practical plasma technology may help overcome the challenges in high-temperature synthesis and enable large-scale electrified plasma manufacturing powered by renewable electricity.

Depolymerization of plastics by means of electrified spatiotemporal heating.

Depolymerization is a promising strategy for recycling waste plastic into constituent monomers for subsequent repolymerization1. However, many commodity plastics cannot be selectively depolymerized using conventional thermochemical approaches, as it is difficult to control the reaction progress and pathway. Although catalysts can improve the selectivity, they are susceptible to performance degradation2. Here we present a catalyst-free, far-from-equilibrium thermochemical depolymerization method that can generate monomers from commodity plastics (polypropylene (PP) and poly(ethylene terephthalate) (PET)) by means of pyrolysis. This selective depolymerization process is realized by two features: (1) a spatial temperature gradient and (2) a temporal heating profile. The spatial temperature gradient is achieved using a bilayer structure of porous carbon felt, in which the top electrically heated layer generates and conducts heat down to the underlying reactor layer and plastic. The resulting temperature gradient promotes continuous melting, wicking, vaporization and reaction of the plastic as it encounters the increasing temperature traversing the bilayer, enabling a high degree of depolymerization. Meanwhile, pulsing the electrical current through the top heater layer generates a temporal heating profile that features periodic high peak temperatures (for example, about 600 °C) to enable depolymerization, yet the transient heating duration (for example, 0.11 s) can suppress unwanted side reactions. Using this approach, we depolymerized PP and PET to their monomers with yields of about 36% and about 43%, respectively. Overall, this electrified spatiotemporal heating (STH) approach potentially offers a solution to the global plastic waste problem.

Atomistic insight into the effects of electrostatic fields on hydrocarbon reaction kinetics.

Reactive Molecular Dynamics (MD) and Density Functional Theory (DFT) computations are performed to provide insight into the effects of external electrostatic fields on hydrocarbon reaction kinetics. By comparing the results from MD and DFT, the suitability of the MD method in modeling electrodynamics is first assessed. Results show that the electric field-induced polarization predicted by the MD charge equilibration method is in good agreement with various DFT charge partitioning schemes. Then, the effects of oriented external electric fields on the transition pathways of non-redox reactions are investigated. Results on the minimum energy path suggest that electric fields can cause catalysis or inhibition of oxidation reactions, whereas pyrolysis reactions are not affected due to the weaker electronegativity of the hydrogen and carbon atoms. MD simulations of isolated reactions show that the reaction kinetics is also affected by applied external Lorentz forces and interatomic Coulomb forces since they can increase or decrease the energy of collision depending on the molecular conformation. In addition, electric fields can affect the kinetics of polar species and force them to align in the direction of field lines. These effects are attributed to energy transfer via intermolecular collisions and stabilization under the external Lorentz force. The kinetics of apolar species is not significantly affected mainly due to the weak induced dipole moment even under strong electric fields. The dynamics and reaction rates of species are studied by means of large-scale combustion simulations of n-dodecane and oxygen mixtures. Results show that under strong electric fields, the fuel, oxidizer, and most product molecules experience translational and rotational acceleration mainly due to close charge transfer along with a reduction in their vibrational energy due to stabilization. This study will serve as a basis to improve the current methods used in MD and to develop novel methodologies for the modeling of macroscale reacting flows under external electrostatic fields.

ReaxFF Force Field Development for Gas-Phase hBN Nanostructure Synthesis.

Two-dimensional (2D) hexagonal boron nitride materials are isomorphs of carbon nanomaterials and hold promise for electronics applications owing to their unique properties. Despite the recent advances in synthesis, the current production capacity for boron nitride (BN) nanostructures is far behind that for carbon-based nanostructures. Understanding the growth mechanism of BN nanostructures through modeling and experiments is key to improving this situation. In the current work, we present the development of a ReaxFF-based force field capable of modeling the gas-phase chemistry important for the chemical vapor deposition (CVD) synthesis process. This force field is parameterized to model the boron nitride nanostructure (BNNS) formation in the gas phase using BN and HBNH as precursors. Our ReaxFF simulations show that BN is the best of these two precursors in terms of quality and the size of BNNSs. The BN precursors lead to the formation of closed BNNSs. However, BNNSs are replaced with complex polymeric structures at temperatures of 2500 K and higher due to entropic effects. Compared to the BN precursors, the HBNH precursors form relatively small, flat, and low-quality BNNSs, but this structure is less affected by temperature. Additives like H2 significantly affect the BNNS formation by preventing closed BNNS formation. Our results show the ReaxFF capability in predicting the BN gas-phase chemistry and BNNS formation, thus providing key insights for experimental synthesis.

Intramuscular depot formulations of leuprolide acetate suppress testosterone levels below a 20 ng/dL threshold: a retrospective analysis of two Phase III studies.

INTRODUCTION: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) analogs is a standard treatment for advanced prostate cancer. GnRH analog therapy can reduce testosterone to "castrate" levels, historically defined as <50 ng/dL. With the advent of newer assays, a lower threshold of <20 ng/dL has recently been proposed. We report the results of a retrospective analysis of two Phase III trials of 4- and 6-month depot microsphere formulations of leuprolide acetate (LA), a GnRH agonist that has previously demonstrated efficacy in testosterone suppression to <50 ng/dL in patients on ADT. This analysis investigates the ability of these LA formulations to suppress to ≤20 ng/dL levels. METHODS: In two of five AbbVie/Abbott clinical trials of microsphere formulations of LA for ADT, analytic technology permitting testosterone detection as low as 3 ng/dL was used and thus was selected for this analysis. Both trials were open-label, fixed-dose studies in prostate cancer patients, naïve to ADT. Patients received either 30 mg (4-month formulation; n=49) or 45 mg (6-month formulation; n=151) depot injections of LA microspheres. Treatment duration was up to 32 weeks for the 4-month formulation and 48 weeks for the 6-month formulation. The proportion of patients achieving the 20 ng/dL threshold was determined every 4 weeks. RESULTS: Pooled analysis showed that 152 of 193 (79%) of patients achieved serum testosterone levels of ≤20 ng/dL at 4 weeks, and sustained the improvement at week 24 (169/189, 89%). Additionally, in the 6-month study, 127/135 (94.1%) patients were suppressed to ≤20 ng/dL at 48 weeks. CONCLUSION: Both 4- and 6-month intramuscular depot formulations of LA achieved and maintained mean serum testosterone levels ≤20 ng/dL in the vast majority of patients as early as 4 weeks following treatment initiation. Additional research on the clinical relevance of this lower testosterone threshold is warranted.

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

OBJECTIVE: 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. APPROACH AND RESULTS: 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%). CONCLUSIONS: Compared with atorvastatin monotherapy, FA plus atorvastatin did not further decrease cIMT progression in high-risk patients with mixed dyslipidemia.

Baseline very low-density lipoprotein cholesterol is associated with the magnitude of triglyceride lowering on statins, fenofibric acid, or their combination in patients with mixed dyslipidemia.

Fibric acid derivatives like fenofibric acid (FA) decrease hepatic production of very low-density lipoprotein (VLDL)-associated triglycerides (TG). Hepatic VLDL production can be estimated from VLDL-associated cholesterol (VLDL-C). We assessed if the degree of TG reduction observed with FA, statins, or their combination is associated with baseline VLDL-C. Overall, 2,715 patients with mixed dyslipidemia in three randomized, controlled studies were assigned to one of six treatment strategies: FA, low-dose statin (LDS), FA + LDS, moderate-dose statin (MDS), FA + MDS, and high-dose statin (HDS). Patients were dichotomized into low- or high-baseline VLDL-C groups. Pooled data were used to compare the degree of TG reduction in patients with low- vs. high-baseline VLDL-C for each treatment arm, using unpaired, two-sided t test. Additionally, the association between baseline VLDL-C level and percentage TG reduction from baseline was evaluated by linear regression. Diagnostic performance of baseline VLDL-C levels in predicting 5, 10, 15, and 20% TG reduction was assessed by receiver operating characteristics (ROC) analysis. In all treatment groups, following 12 weeks of therapy, a significantly greater percent change from baseline in TG was observed in the high-baseline VLDL-C group as compared with the low-baseline VLDL-C group. Linear regression analysis indicated that approximately 6 to 13% of the decrease in TG could be explained by baseline VLDL-C. ROC-derived cut points for baseline VLDL-C were obtained for 5, 10, 15, and 20% TG reduction. Baseline VLDL-C levels are associated with the degree of TG lowering using FA, statins, or their combination, thereof.

A randomized, double-blind study of fenofibric acid plus rosuvastatin compared with rosuvastatin alone in stage 3 chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) often have mixed dyslipidemia and high cardiovascular disease risk. Although statins reduce LDL-C, adding a fibrate may further improve lipid parameters. OBJECTIVE: This multicenter, randomized study evaluated the short-term efficacy and safety profile of fenofibric acid (FA) + rosuvastatin (R) combination therapy for improving lipid parameters in patients with stage 3 CKD and mixed dyslipidemia. The study also assessed estimated glomerular filtration rate after study drug washout. METHODS: Patients received FA 45 mg + R (5 mg for 8 weeks, then 10 mg for 8 additional weeks) or R monotherapy (5 mg for 8 weeks, then 10 mg for 8 additional weeks), followed by an 8-week washout period. Primary and secondary end points were percent changes in triglycerides and HDL-C, respectively, from baseline to week 8. RESULTS: FA 45 mg + R 5 mg, compared with R 5 mg, resulted in significant improvements in triglycerides (median % changes: week 8, -38.0% vs -22.4%, P < 0.001; week 16, -42.6% vs -29.7%, P < 0.001) and HDL-C (mean % changes: week 8, 16.9% vs 7.8%, P < 0.001; week 16, 17.3% vs 8.9%, P < 0.001). Adverse event rates were similar between groups (70.7% with FA + R vs 68.6% with R). Mean serum creatinine level at baseline was 1.36 mg/dL in the FA + R group and 1.38 mg/dL in the R group. The final treatment serum creatinine value, defined as the last nonmissing postbaseline value collected within 30 days after the last dose of study drug, was 1.52 mg/dL with FA + R (vs 1.41 mg/dL with R; P < 0.001), which then decreased to 1.39 mg/dL after the 8-week washout (vs 1.42 mg/dL with R). CONCLUSIONS: The data suggest that, after 16 weeks of therapy, FA + R has an acceptable safety profile and improved TG and HDL-C efficacy versus R. FA + R combination therapy may thus further improve lipid parameters in patients with stage 3 CKD and mixed dyslipidemia. ClinicalTrials.gov identifier: NCT00680017.

Attainment of goal/desirable lipid levels in patients with mixed dyslipidemia after 12 weeks of treatment with fenofibric acid and rosuvastatin combination therapy: a pooled analysis of controlled studies.

BACKGROUND: Goal/desirable lipid levels are underachieved in patients with mixed dyslipidemia. These patients may have substantial residual risk of cardiovascular disease even while receiving optimal LDL-C-lowering therapy and may require additional therapy to improve multiple lipid/lipoprotein levels. OBJECTIVE: To evaluate attainment of goal/desirable levels of lipids/lipoproteins after 12-week treatment with combination rosuvastatin + fenofibric acid versus rosuvastatin monotherapy. METHODS: This was a post hoc analysis of patients with mixed dyslipidemia who enrolled in one of two randomized controlled trials, and were treated (N = 2066) with rosuvastatin (5, 10, or 20 mg), fenofibric acid 135 mg, or rosuvastatin + fenofibric acid for 12 weeks. Data were pooled across doses of rosuvastatin as monotherapy and combination therapy. RESULTS: Compared with rosuvastatin monotherapy, combination therapy had comparable effects in achieving risk-stratified LDL-C goals; however, measures of total atherogenic burden were improved because significantly greater percentages of patients attained non-HDL-C goal in high- (62.9% vs 50.4%, P = .006) and moderate-risk groups (87.6% vs 80.4%, P = .016) and apolipoprotein B (ApoB) <90 mg/dL in high-risk group (59.8% vs 43.8%, P < .001). In the overall population, more patients treated with the combination therapy achieved desirable levels of HDL-C >40/50 mg/dL in men/women (P < .001), triglycerides <150 mg/dL (P < .001), and ApoB <90 mg/dL (P < .001), compared with rosuvastatin monotherapy. Furthermore, combination therapy resulted in significantly greater percentages of patients achieving simultaneous specified levels of LDL-C + non-HDL-C (P < .015); LDL-C + HDL-C + TG (P < .001); and LDL-C + HDL-C + triglycerides + non-HDL-C + ApoB (P < .001), compared with rosuvastatin monotherapy. CONCLUSION: Rosuvastatin + fenofibric acid may be more efficacious than rosuvastatin alone in patients with mixed dyslipidemia.

Long-term efficacy of adding fenofibric acid to moderate-dose statin therapy in patients with persistent elevated triglycerides.

OBJECTIVE: The objective of this study was to evaluate the long-term efficacy of adding fenofibric acid to moderate-dose statin therapy in patients at goal for low-density lipoprotein cholesterol (LDL-C) but with persistent hypertriglyceridemia. METHODS: This is a post hoc analysis of a subset of patients (N = 92) with mixed dyslipidemia treated with moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg, or atorvastatin 40 mg) for 12 weeks in three controlled trials who had achieved LDL-C <100 mg/dL but whose triglycerides remained >200 mg/dL, and had fenofibric acid 135 mg added to the moderate-dose statin in a 52-week open-label extension study. Lipid and apolipoprotein (Apo) values and the proportion of patients meeting individual and combined treatment targets with combination therapy were determined at scheduled visits during the 52-week study and compared with baseline (start of extension study). RESULTS: Addition of fenofibric acid to moderate-dose statin for 52 weeks resulted in significant (P < 0.001) improvements in non-high-density lipoprotein cholesterol (non-HDL-C; -9.0%), ApoB (-9.8%), HDL-C (14.9%), and triglycerides (-37.6%) compared with baseline. At final visit, greater proportions of patients achieved optimal levels of individual parameters as well as combined targets of LDL-C + non-HDL-C (60.0% vs 52.2%), LDL-C + non-HDL-C + ApoB (53.3% vs 37.8%, P = 0.007), and LDL-C + non-HDL-C + ApoB + HDL-C + triglycerides (25.6% vs 0.0%) than at baseline. CONCLUSIONS: The addition of fenofibric acid to moderate-dose statin in patients whose LDL-C was optimal but whose triglycerides remained >200 mg/dL led to additional improvements in non-HDL-C, ApoB, HDL-C, and triglycerides that resulted in greater proportions of patients attaining optimal levels of the individual parameters as well as simultaneously achieving optimal levels of these parameters and LDL-C.

Efficacy of fenofibric acid plus statins on multiple lipid parameters and its safety in women with mixed dyslipidemia.

The combination of fibrate and statin therapies may be a treatment option for women with multiple lipid abnormalities. We, therefore, initiated the present safety and efficacy analysis to address the paucity of such data in women with mixed dyslipidemia. A total of 1,393 women with mixed dyslipidemia (low-density lipoprotein [LDL] cholesterol ≥ 130 mg/dl, triglycerides [TG] ≥ 150 mg/dl, high-density lipoprotein [HDL] cholesterol <50 mg/dl), who had enrolled in any 1 of 3 randomized clinical trials, were evaluated. The eligible women were randomized to receive fenofibric acid plus a low- or moderate-dose statin (combination treatment); or low-, moderate-, or high-dose statin monotherapy; or fenofibric acid monotherapy. With low-dose combination treatment, the baseline HDL cholesterol level increased 20% and TG decreased 46% compared to an 8% HDL cholesterol increase and 20% TG decrease with low-dose statins alone. With the moderate-dose combination, the baseline HDL cholesterol increased 21% and TG decreased 44% compared to an 8% HDL cholesterol increase and 26% TG decrease with moderate-dose statins alone. The reduction in baseline LDL cholesterol with low-dose and moderate-dose combinations (37% and 39%, respectively) was comparable to the reduction with corresponding-dose statins (36% and 43%, respectively). High-dose statins decreased the baseline LDL cholesterol 47%; however, the increase in HDL cholesterol (9%) and decrease in TG (25%) were similar to the changes observed with lower doses of statins. The safety profiles of the combinations were comparable to those of the component therapies. In conclusion, these data suggest that a combination of fenofibric acid and a statin could be considered safe and efficacious for treating women with mixed dyslipidemia.

Year two assessment of fenofibric acid and moderate-dose statin combination: a phase 3, open-label, extension study.

BACKGROUND AND OBJECTIVES: Long-term (>1 year) safety and efficacy studies of combination lipid therapy are lacking. This year 2 study evaluated fenofibric acid 135 mg in combination with moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg) in patients with mixed dyslipidaemia. METHODS: This was a phase 3, open-label, year 2 extension study in patients who had completed one of three double-blind, 12-week, controlled studies and the subsequent open-label, year 1 extension study. Patients in this study had mixed dyslipidaemia (high-density lipoprotein cholesterol [HDL-C] <40 mg/dL [<1.02 mmol/L] for men or <50 mg/dL [<1.28 mmol/L] for women, triglycerides [TG] > or =150 mg/dL [> or =1.69 mmol/L], and low-density lipoprotein cholesterol [LDL-C] > or =130 mg/dL [> or =3.37 mmol/L]) at the start of the controlled study, and had completed the year 1 extension study. Treatment was once-daily oral coadministration of fenofibric acid 135 mg and moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg), and was identical to the treatment received in the year 1 study. The year 2 population safety data were summarized for the entire duration of fenofibric acid + statin therapy. Efficacy data were summarized by combination therapy group, as well as pooled across combination therapies, and summarized across the controlled and open-label studies. RESULTS: Of the 310 patients enrolled into the year 2 study, 287 (93%) completed therapy. The mean cumulative exposure to combination therapy was 743 days across the studies. Adverse event rates were similar for all three combination therapy groups. No deaths or treatment-related serious adverse events occurred. The incidence of discontinuation due to adverse events was 2.9% overall. Rhabdomyolysis was not reported in any group. Overall, fenofibric acid + moderate-dose statin for > or =2 years resulted in sustained improvements in HDL-C (+17.4%), TG (-46.4%) and LDL-C (-40.4%). CONCLUSIONS: This long-term study demonstrated that fenofibric acid + moderate-dose statin was generally well tolerated with no new or unexpected safety concerns, and resulted in comprehensive and sustained lipid improvements in patients with mixed dyslipidaemia.

Efficacy and safety of fenofibric acid in combination with a statin in patients with mixed dyslipidemia: Pooled analysis of three phase 3, 12-week randomized, controlled studies.

BACKGROUND: Patients with mixed dyslipidemia often require combination therapy to manage multiple lipid abnormalities. OBJECTIVE: To evaluate fenofibric acid in combination with a statin across three studies of patients with mixed dyslipidemia. METHODS: As prospectively planned, data were pooled from three randomized, double-blind, phase 3 studies of patients with low-density lipoprotein cholesterol (LDL-C) ≥130mg/dL, triglycerides (TG) ≥150mg/dL, and high-density lipoprotein cholesterol (HDL-C) <40mg/dL (men) or <50mg/dL (women). A total of 2715 patients were randomly assigned to 12-week treatment with fenofibric acid 135mg monotherapy; low-, moderate-, or high-dose statin (rosuvastatin, simvastatin, or atorvastatin, depending on study) monotherapy; or fenofibric acid + low- or moderate-dose statin. The primary efficacy comparisons were mean percent change in HDL-C and TG (combination therapy vs. statin) and LDL-C (combination therapy vs. fenofibric acid). RESULTS: Fenofibric acid + low-dose statin increased HDL-C (18.1% vs. 7.4%) and reduced TG (-43.9% vs. -16.8%) versus low-dose statin monotherapy and reduced LDL-C (-33.1% vs. -5.1%) versus fenofibric acid monotherapy (P <.001 for all). Fenofibric acid + moderate-dose statin increased HDL-C (17.5% vs. 8.7%) and reduced TG (-42.0% vs. -23.7%) versus moderate-dose statin monotherapy and reduced LDL-C (-34.6% vs. -5.1%) versus fenofibric acid monotherapy (P <.001 for all). Combination therapy was generally well tolerated, and safety profiles were similar to monotherapies. No rhabdomyolysis was reported. CONCLUSION: In patients with mixed dyslipidemia, combination therapy simultaneously improved multiple lipid abnormalities more effectively than fenofibric acid or statin monotherapies.