Trilipix (Choline Fenofibrate) - Description and Clinical Pharmacology

DESCRIPTION

Trilipix (fenofibric acid) is a lipid regulating agent available as delayed release capsules for oral administration. Each delayed release capsule contains choline fenofibrate, equivalent to 45 mg or 135 mg of fenofibric acid. The chemical name for choline fenofibrate is ethanaminium, 2-hydroxy-N,N,N-trimethyl, 2-{4-(4-chlorobenzoyl)phenoxy] -2-methylpropanoate (1:1) with the following structural formula:

The empirical formula is C₂₂H₂₈ClNO₅ and the molecular weight is 421.91. Choline fenofibrate is freely soluble in water. The melting point is approximately 210°C. Choline fenofibrate is a white to yellow powder, which is stable under ordinary conditions.

Each delayed release capsule contains enteric coated mini-tablets comprised of choline fenofibrate and the following inactive ingredients: hypromellose, povidone, water, hydroxylpropyl cellulose, colloidal silicon dioxide, sodium stearyl fumarate, methacrylic acid copolymer, talc, triethyl citrate. The capsule shell of the 45 mg capsule contains the following inactive ingredients: gelatin, titanium dioxide, yellow iron oxide, black iron oxide, and red iron oxide. The capsule shell of the 135 mg capsule contains the following inactive ingredients: gelatin, titanium dioxide, yellow iron oxide, and FD&C Blue #2.

CLINICAL PHARMACOLOGY

Mechanism of Action

The active moiety of Trilipix is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate.

The lipid-modifying effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, fenofibric acid increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of Apo CIII (an inhibitor of lipoprotein lipase activity).

The resulting decrease in TG produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of HDL-C and Apo AI and AII.

Pharmacodynamics

Elevated levels of Total-C, LDL-C, and Apo B, and decreased levels of HDL-C and its transport complex, Apo AI and Apo AII, are risk factors for human atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the levels of Total-C, LDL-C, and TG, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering TG on the risk of cardiovascular morbidity and mortality has not been determined.

Pharmacokinetics

Trilipix contains fenofibric acid, which is the only circulating pharmacologically active moiety in plasma after oral administration of Trilipix. Fenofibric acid is also the circulating pharmacologically active moiety in plasma after oral administration of fenofibrate, the ester of fenofibric acid.

Plasma concentrations of fenofibric acid after administration of one 135 mg Trilipix delayed release capsule are equivalent to those after one 200 mg capsule of micronized fenofibrate administered under fed conditions.

Absorption
Fenofibric acid is well absorbed throughout the gastrointestinal tract. The absolute bioavailability of fenofibric acid is approximately 81%.

Peak plasma levels of fenofibric acid occur within 4 to 5 hours after a single dose administration of Trilipix capsule under fasting conditions.

Fenofibric acid exposure in plasma, as measured by C_max and AUC, is not significantly different when a single 135 mg dose of Trilipix is administered under fasting or nonfasting conditions.

Distribution
Upon multiple dosing of Trilipix, fenofibric acid levels reach steady state within 8 days. Plasma concentrations of fenofibric acid at steady state are approximately slightly more than double those following a single dose. Serum protein binding is approximately 99% in normal and dyslipidemic subjects.

Metabolism
Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.

In vivo metabolism data after fenofibrate administration indicate that fenofibric acid does not undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.

Excretion
After absorption, Trilipix is primarily excreted in the urine in the form of fenofibric acid and fenofibric acid glucuronide.

Fenofibric acid is eliminated with a half-life of approximately 20 hours, allowing once daily administration of Trilipix.

Specific Populations
Geriatrics
In five elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that an equivalent dose of Trilipix can be used in elderly subjects with normal renal function, without increasing accumulation of the drug or metabolites [see USE IN SPECIFIC POPULATIONS ].

Pediatrics
Trilipix has not been investigated in adequate and well-controlled trials in pediatric patients.

Gender
No pharmacokinetic difference between males and females has been observed for Trilipix.

Race
The influence of race on the pharmacokinetics of Trilipix has not been studied.

Renal Impairment
The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (creatinine clearance [CrCl] < 30 mL/min showed a 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (CrCl 30-80 mL/min) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of Trilipix should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment.

Hepatic Impairment
No pharmacokinetic studies have been conducted in patients with hepatic impairment.

Drug-drug Interactions
In vitro studies using human liver microsomes indicate that fenofibric acid is not an inhibitor of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. It is a weak inhibitor of CYP2C8, CYP2C19, and CYP2A6, and mild-to-moderate inhibitor of CYP2C9 at therapeutic concentrations.

Table 3 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 4 describes the effects of co-administered fenofibric acid on other drugs.

Table 3. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Trilipix or Fenofibrate Administration

Co-Administered Drug	Dosage Regimen of Co-Administered Drug	Dosage Regimen of Trilipix or Fenofibrate	Changes in Fenofibric Acid Exposure
			AUC	Cmax
No dosing adjustment required for Trilipix with the following co-administered drugs
Lipid-lowering agents
Rosuvastatin	40 mg QD for 10 days	Trilipix 135 mg QD for 10 days	↓2%	↓2%
Atorvastatin	20 mg QD for 10 days	Fenofibrate 160 mg1 QD for 10 days	↓2%	↓4%
Pravastatin	40 mg as a single dose	Fenofibrate 3 x 67 mg2 as a single dose	↓1%	↓2%
Fluvastatin	40 mg as a single dose	Fenofibrate 160 mg1 as a single dose	↓2%	↓10%
Simvastatin	80 mg QD for 7 days	Fenofibrate 160 mg1 QD for 7 days	↓5%	↓11%
Ezetimibe	10 mg QD for 10 days	Fenofibrate 145 mg1 QD for 10 days	0%	↑3%
Anti-diabetic agents
Glimepiride	1 mg as a single dose	Fenofibrate 145 mg1 QD for 10 days	↑1%	↓1%
Metformin	850 mg TID for 10 days	Fenofibrate 54 mg1 TID for 10 days	↓9%	↓6%
Rosiglitazone	8 mg QD for 5 days	Fenofibrate 145 mg1 QD for 14 days	↑10%	↑3%
Gastrointestinal agents
Omeprazole	40 mg QD for 5 days	Trilipix 135 mg as a single dose fasting	↑6%	↑17%
Omeprazole	40 mg QD for 5 days	Trilipix 135 mg as a single dose with food	↑4%	↓2%
1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule

Table 4. Effects of Trilipix or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs

Dosage Regimen of Trilipix or Fenofibrate	Dosage Regimen of Co-Administered Drug	Change in Co-Administered Drug Exposure
		Analyte	AUC	Cmax
No dosing adjustments required for these co-administered drugs with Trilipix
Lipid-lowering agents
Trilipix 135 mg QD for 10 days	Rosuvastatin, 40 mg QD for 10 days	Rosuvastatin	↑6%	↑20%
Fenofibrate 160 mg1 QD for 10 days	Atorvastatin, 20 mg QD for 10 days	Atorvastatin	↓17%	0%
Fenofibrate 3 x 67 mg2 as a single dose	Pravastatin, 40 mg as a single dose	Pravastatin	↑13%	↑13%
		3α-Hydroxyl-iso-pravastatin	↑26%	↑29%
Fenofibrate 160 mg1 QD for 10 days	Pravastatin, 40 mg QD for 10 days	Pravastatin	↑28%	↑36%
		3α-Hydroxyl-iso-pravastatin	↑39%	↑55%
Fenofibrate 160 mg1 as a single dose	Fluvastatin, 40 mg as a single dose	(+)-3R, 5S-Fluvastatin	↑15%	↑16%
Fenofibrate 160 mg1 QD for 7 days	Simvastatin, 80 mg QD for 7 days	Simvastatin acid	↓36%	↓11%
		Simvastatin	↓11%	↓17%
		Active HMG-CoA Inhibitors	↓12%	↓1%
		Total HMG-CoA Inhibitors	↓8%	↓10%
Fenofibrate 145 mg1 QD for 10 days	Ezetimibe, 10 mg QD for 10 days	Total Ezetimibe	↑43%	↑33%
		Free Ezetimibe	↑3%	↑11%
		Ezetimibe Glucuronide	↑49%	↑34%
Anti-diabetic agents
Fenofibrate 145 mg1 QD for 10 days	Glimepiride, 1 mg as a single dose	Glimepiride	↑35%	↑18%
Fenofibrate 54 mg1 TID for 10 days	Metformin, 850 mg TID for 10 days	Metformin	↑3%	↑6%
Fenofibrate 145 mg1 QD for 14 days	Rosiglitazone, 8 mg QD for 5 days	Rosiglitazone	↑6%	↓1%
1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Trilipix (fenofibric acid)

No carcinogenicity and fertility studies have been conducted with choline fenofibrate or fenofibric acid. However, because fenofibrate is rapidly converted to its active metabolite, fenofibric acid, either during or immediately following absorption both in animals and humans, studies conducted with fenofibrate are relevant for the assessment of the toxicity profile of fenofibric acid. A similar toxicity spectrum is expected after treatment with either Trilipix or fenofibrate.

Fenofibrate

Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, rats were dosed with fenofibrate at 10, 45, and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m²). At a dose of 200 mg/kg/day (6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males.

A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m² surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes and testicular interstitial cell tumors in males at 2 times the MRHD. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males.

In an 80-week study in mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m² surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 93-week study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male and female mice at 3 times the MRHD.

Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual.

Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, and micronucleus in vivo /rat. In addition, fenofibric acid, has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and sister chromatid exchange in human lymphocytes, and unscheduled DNA synthesis in primary rat hepatocytes.

In a fertility study, rats were given oral dietary doses of fenofibrate. Males received doses for 61 days prior to mating and females for 15 days prior to mating through weaning, which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~10 times the MRHD, based on mg/m² surface area comparisons).

CLINICAL STUDIES

Co-Administration Therapy with Statins

Efficacy and safety of Trilipix co-administered with statins were assessed in three 12-week, double-blind, controlled Phase 3 studies and one 52-week, long-term, open-label extension study in 2698 patients with mixed dyslipidemia. Patients were required to meet the following fasting lipid entry criteria: TG ≥ 150 mg/dL, and HDL-C < 40 mg/dL (males) and < 50 mg/dL (females), and LDL-C≥ 130 mg/dL. The three multicenter, randomized, double-blind, controlled studies had similar designs, differing primarily in the statin used for combination therapy/monotherapy. Each study compared the effects of 135 mg Trilipix co-administered with either a low dose or a moderate dose of statin with Trilipix monotherapy and statin monotherapy at the corresponding dose on CHD lipid risk factors. A smaller group of patients received a high dose of statin monotherapy. In study 1, patients received Trilipix co-administered with 10 mg or 20 mg rosuvastatin. In study 2, patients received Trilipix co-administered with 20 mg or 40 mg simvastatin. In study 3, patients received Trilipix co-administered with 20 mg or 40 mg atorvastatin.

Patients were enrolled for a total of approximately 22 weeks, consisting of a 6-week diet run-in/washout period, a 12-week treatment period, and a 30-day safety follow up period. Patients who completed the 12-week treatment period were eligible to participate in the 52-week long-term extension study. Of the 2698 randomized and treated subjects in the controlled studies, 51.6% were female and 48.4% were male; 92.6% of all subjects were White, 4.7% were Black, and 2.8% were of other races. Hispanics comprised 9.9% of the study population. Mean age was 54.9 years.

The primary efficacy endpoints for all three studies were mean percent changes from baseline to final value in HDL-C, TG, and LDL-C. For each statin dose co-administered with Trilipix, there were three primary comparisons. For HDL-C and TG, Trilipix co-administered with each statin dose was compared with statin monotherapy at the corresponding dose. For LDL-C, Trilipix co-administered with each statin dose was compared with Trilipix monotherapy. In order to declare combination therapy successful for a particular statin dose, all three primary comparisons were required to demonstrate superiority of the combination therapy over the corresponding monotherapy. The primary efficacy results were consistent in the three studies and were confirmed by the pooled analysis of the three studies. The results from the individual studies and the pooled analysis demonstrated that Trilipix co-administered with low-dose statins and moderate-dose statins was superior to the corresponding monotherapy. Statistically significant differences were observed for all three primary efficacy comparisons for both doses of combination therapy in all three double-blind, controlled studies as well as the pooled analysis.

In the pooled analysis, Trilipix co-administered with both low-dose statins and moderate-dose statins resulted in mean percent increases (18.1% and 17.5%) in HDL-C and mean percent decreases (-43.9% and -42.0%) in TG that were significantly greater than the corresponding dose of statin monotherapy (7.4% and 8.7% for HDL-C; -16.8% and -23.7% for TG). In addition, both doses of combination therapy resulted in mean percent decreases (-33.1% and -34.6%) in LDL-C that were significantly greater than Trilipix monotherapy (-5.1%). The results of the pooled analysis are described in Table 5.

Table 5. Mean Percent Change from Baseline to the Final Value in HDL-C, TG, and LDL-C (Pooled Double-Blind, Controlled Studies)

	Trilipix	Low-Dose Statin	Trilipix + Low-Dose Statin	Between-group ∆ (p-value)	Moderate-Dose Statin	Trilipix + Moderate-Dose Statin	Between-group ∆ (p-value)	High-Dose Statin
a Combination therapy vs. corresponding statin monotherapy b Combination therapy vs. Trilipix monotherapy Low-dose statin = rosuvastatin 10 mg, simvastatin 20 mg, or atorvastatin 20 mg Moderate-dose statin = rosuvastatin 20 mg, simvastatin 40 mg, or atorvastatin 40 mg High-dose statin = rosuvastatin 40 mg, simvastatin 80 mg, or atorvastatin 80 mg BL = Baseline % ∆ = Percent change from baseline to final value
HDL-C (mg/dL)	(N = 420)	(N = 455)	(N = 423)		(N = 430)	(N = 422)		(N = 217)
BL mean	38.4	38.4	38.2		38.4	38.1		38.0
Mean % ∆	16.3%	7.4%	18.1%	10.7%a (< 0.001)	8.7%	17.5%	8.8%a (< 0.001)	7.9%
TG (mg/dL)	(N = 459)	(N = 477)	(N = 470)		(N = 472)	(N = 462)		(N = 235)
BL mean	280.7	286.1	282.1		287.9	286.1		282.5
Mean % ∆	-31.0%	-16.8%	-43.9%	-27.2%a (< 0.001)	-23.7%	-42.0%	-18.3%a (< 0.001)	-28.1%
LDL-C (mg/dL)	(N = 427)	(N = 463)	(N = 436)		(N = 439)	(N = 434)		(N = 225)
BL mean	158.4	153.8	155.7		158.0	156.4		156.1
Mean % ∆	-5.1%	-33.9%	-33.1%	-28.0%b (< 0.001)	-40.6%	-34.6%	-29.5%b (< 0.001)	-47.1%

Secondary efficacy endpoints in all three double-blind, controlled studies were percent changes in non-HDL-C (Trilipix co-administered with statin compared to Trilipix monotherapy and corresponding statin monotherapy), and percent changes in VLDL-C, Total-C, and Apo B (Trilipix co-administered with statin compared to corresponding statin monotherapy). Co-administration of Trilipix with statins resulted in the following changes in secondary parameters (Table 6).

Table 6. Percent Change from Baseline to the Final Value in Non-HDL-C, VLDL-C, Total-C, and Apo B (Pooled Double-Blind, Controlled Studies)

Secondary Endpoints	Trilipix	Low-Dose Statin	Trilipix + Low-Dose Statin	Between-group ∆	Moderate-Dose Statin	Trilipix + Moderate-Dose Statin	Between-group ∆	High-Dose Statin
a Trilipix + statin vs. Trilipix monotherapy b Trilipix + statin vs. corresponding statin monotherapy Low-dose statin = rosuvastatin 10 mg, simvastatin 20 mg, or atorvastatin 20 mg Moderate-dose statin = rosuvastatin 20 mg, simvastatin 40 mg, or atorvastatin 40 mg High-dose statin = rosuvastatin 40 mg, simvastatin 80 mg, or atorvastatin 80 mg BL = Baseline % ∆ = Percent change from baseline to final value
Non HDL-C (mg/dL)	(N = 420)	(N = 454)	(N = 422)		(N = 431)	(N = 420)		(N = 217)
BL mean	222.5	217.6	219.9		222.4	218.9		220.2
Mean % ∆	-17.3%	-34.9%	-40.4%	-23.1%a -5.5%b	-42.4%	-42.0%	-24.8%a 0.4%b	-47.3%
VLDL-C (mg/dL)	(N = 449)	(N = 463)	(N = 455)		(N = 458)	(N = 449)		(N = 232)
BL mean	65.0	66.0	65.5		67.8	64.5		66.1
Mean % ∆	-34.2%	-32.1%	-50.0%	-18.0%b	-38.9%	-51.2%	-12.3%b	-42.1%
Total-C (mg/dL)	(N = 459)	(N = 477)	(N = 469)		(N = 472)	(N = 462)		(N = 235)
BL mean	260.9	257.0	258.6		261.3	257.3		258.8
Mean % ∆	-12.4%	-28.7%	-31.5%	-2.8%b	-34.7%	-33.3%	1.4%b	-39.5%
Apo B (mg/dL)	(N = 455)	(N = 470)	(N = 465)		(N = 468)	(N = 455)		(N = 229)
BL mean	146.2	145.0	146.1		147.1	145.0		146.0
Mean % ∆	-15.6%	-31.1%	-36.3%	-5.2%b	-36.9%	-36.7%	0.2%b	-42.4%

A total of 1895 patients who completed 12 weeks of treatment in the double-blind, controlled studies were treated in the 52-week, long-term extension study. Patients received Trilipix co-administered with the moderate-dose of the statin that had been used in the double-blind, controlled study in which they were enrolled. Whether combination therapy was initiated during the double-blind, controlled studies or introduced during the long-term extension study, the treatment effect of combination therapy was observed within four weeks, and was sustained over the duration of treatment in the long-term study. A total of 568 patients completed 52 weeks of treatment with Trilipix co-administered with statins. Mean 52-week values and mean percent change from baseline (at time of enrollment in randomized controlled trials) were 91.7 mg/dL (-38.2%) for LDL-C, 47.3 mg/dL (+24.0%) for HDL-C, 135.5 mg/dL (-47.6%) for TG, 117.9 mg/dL (-45.7%) for non-HDL-C, 26.2 mg/dL (-53.1%) for VLDL-C, 165.2 mg/dL (-35.4%) for Total-C, and 81.4 mg/dL (-43.6%) for Apo B.

Hypertriglyceridemia

The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 500 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 135 mg once daily of Trilipix decreased primarily VLDL-TG and VLDL-C. Treatment of patients with elevated TG often results in an increase of LDL-C (Table 7).

Table 7. Effects of Fenofibrate in Patients With Hypertriglyceridemia

* = p < 0.05 vs. Placebo
Study 1	Placebo				Fenofibrate
Baseline TG levels 350 to 499 mg/dL	N	Baseline Mean (mg/dL)	Endpoint Mean (mg/dL)	Mean % Change	N	Baseline Mean (mg/dL)	Endpoint Mean (mg/dL)	Mean % Change
Triglycerides	28	449	450	-0.5	27	432	223	-46.2*
VLDL Triglycerides	19	367	350	2.7	19	350	178	-44.1*
Total Cholesterol	28	255	261	2.8	27	252	227	-9.1*
HDL Cholesterol	28	35	36	4	27	34	40	19.6*
LDL Cholesterol	28	120	129	12	27	128	137	14.5
VLDL Cholesterol	27	99	99	5.8	27	92	46	-44.7*
Study 2	Placebo				Fenofibrate
Baseline TG levels 500 to 1500 mg/dL	N	Baseline Mean (mg/dL)	Endpoint Mean (mg/dL)	Mean % Change	N	Baseline Mean (mg/dL)	Endpoint Mean (mg/dL)	Mean % Change
Triglycerides	44	710	750	7.2	48	726	308	-54.5*
VLDL Triglycerides	29	537	571	18.7	33	543	205	-50.6*
Total Cholesterol	44	272	271	0.4	48	261	223	-13.8*
HDL Cholesterol	44	27	28	5.0	48	30	36	22.9*
LDL Cholesterol	42	100	90	-4.2	45	103	131	45.0*
VLDL Cholesterol	42	137	142	11.0	45	126	54	-49.4*

Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia

The effects of fenofibrate at a dose equivalent to Trilipix 135 mg once daily were assessed from four randomized, placebo-controlled, double-blind, parallel-group studies including patients with the following mean baseline lipid values: Total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL. Fenofibrate therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate therapy also lowered triglycerides and raised HDL-C (Table 8).

Table 8. Mean Percent Change in Lipid Parameters at End of Treatment^†

Treatment Group	Total-C (mg/dL)	LDL-C (mg/dL)	HDL-C (mg/dL)	TG (mg/dL)
†   Duration of study treatment was 3 to 6 months *   p = < 0.05 vs. Placebo
Pooled Cohort
Mean baseline lipid values (n = 646)	306.9	213.8	52.3	191.0
All Fenofibrate (n = 361)	-18.7%*	-20.6%*	+11.0%*	-28.9%*
Placebo (n = 285)	-0.4%	-2.2%	+0.7%	+7.7%
Baseline LDL-C > 160 mg/dL and TG < 150 mg/dL
Mean baseline lipid values (n = 334)	307.7	227.7	58.1	101.7
All Fenofibrate (n = 193)	-22.4%*	-31.4%*	+9.8%*	-23.5%*
Placebo (n = 141)	+0.2%	-2.2%	+2.6%	+11.7%
Baseline LDL-C > 160 mg/dL and TG ≥ 150 mg/dL
Mean baseline lipid values (n = 242)	312.8	219.8	46.7	231.9
All Fenofibrate (n = 126)	-16.8%*	-20.1%*	+14.6%*	-35.9%*
Placebo (n = 116)	-3.0%	-6.6%	+2.3%	+0.9%

In a subset of the subjects, measurements of Apo B were conducted. Fenofibrate treatment significantly reduced Apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p < 0.0001, n = 213 and 143, respectively).