Drug Evaluation
v-3 carboxylic acids for hypertriglyceridemia
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Louisville on 12/30/14 For personal use only.
Eli M Roth University of Cincinnati & Sterling Research Group, Cincinnati, OH, USA
1.
Introduction
2.
Body of review
3.
Clinical efficacy
4.
Safety and tolerability
5.
Regulatory affairs
6.
Conclusion
7.
Expert opinion
Introduction: w-3 carboxylic acids (w3 CA), also called w3 free fatty acids (w3 FFA), with the trade name Epanova is a new formulation of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) approved for the treatment of severe hypertriglyceridemia. The FFA form of EPA and DHA is associated with higher bioavailability than other forms of w3 fatty acids, potentially resulting in efficacy at lower doses and less dependence on meal relationship. Areas covered: The efficacy and safety of w3 CA from clinical trials as well as PK and PD data will be reviewed. The mechanism of action of w3 fatty acids in the lowering of triglycerides (TG) will be discussed and comparison is made with w3 ethyl ester compounds. Expert opinion: w3 CA are a unique form of w3 fatty acids that appear safe and effective in lowering serum TG and offer the possibility of better patient compliance due to lower-dose efficacy and the ability to take with or without food. w3 CA lowered TG by 26 and 31% for the 2 and 4 g/day doses, respectively, and Apo CIII was also lowered 11 and 14%, respectively, as well. Keywords: DHA, EPA, Epanova, fish oil, w-3, w-3 carboxylic acids, w-3 free fatty acids, triglycerides Expert Opin. Pharmacother. (2015) 16(1):123-133
1.
Introduction
Hypertriglyceridemia and v-3 compounds Hypertriglyceridemia is increasing in the US and throughout the world, with an estimated prevalence of four million Americans meeting the definition of severe hypertriglyceridemia (‡ 500 mg/dl) [1]. The US FDA approves the use of prescription w-3 compounds to lower triglyceride (TG) only for very high levels (‡ 500 mg/ dl) but notes the effect on the risk of pancreatitis or morbidity or mortality of cardiovascular disease (CVD) has not been determined. Although severe hypertriglyceridemia appears to be a causal factor for acute pancreatitis, there has never been a clinical study performed to show that lowering TG is beneficial. The ATP III guidelines recommended that once low-density lipoprotein cholesterol (LDL-C) level was at target, that a TG ‡ 200 mg/dl should be treated [2]. The guidelines from the European Society of Cardiology state that CVD risk is increased if fasting TG are ‡ 1.7 mmol/l (‡ 150 mg/dl), but that drugs to lower TG should only be considered if TG is ‡ 2.3 mmol/l (‡ 200 mg/dl) and the patient is at high CVD risk and cannot lower their TG by lifestyle measures [3,4]. 1.1
Hypertriglyceridemia and CVD The last official US guideline to deal with the definition of hypertriglyceridemia was the National Cholesterol Education Program -- Adult Treatment Panel III (NCEP ATPIII) in 2001, which defined normal TG level as < 150 mg/dl, borderline high as 150 -- 199 mg/dl, high as 200 -- 499 mg/dl and very high TG as ‡ 500 mg/dl [2]. The ATP III TG definitions were considerably lower than the previous ATP II TG levels (Table 1). The 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines on the Treatment of Blood Cholesterol to 1.2
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Box 1. Drug summary. Drug name
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Phase Indication Pharmacology description
Route of administration Chemical structure
Trials
w-3 carboxylic acid (w3 CA) or w-3 free fatty acid (w3 FFA) Approved in the US Hypertriglyceridemia (‡ 500 mg/dl) w3s decrease the hepatic synthesis of VLDL, increase beta oxidation of fatty acids thus decreasing their availability for TG synthesis, and enhance the clearance of TG from VLDL particles and chylomicrons by increasing LPL activity Oral Eicosapentaenoic acid (EPA) (C20:5n-3) and docosahexaenoic acid (DHA) (C22:6n-3) ECLIPSE, ECLIPSE II, EVOLVE, ESPRIT
Reduce Atherosclerotic Cardiovascular Risk in Adults (formerly ATP IV) did not deal with TG, as the panel felt that good data were lacking to make recommendations [5]. Epidemiologic data have long supported the concept that an elevated TG level is a risk factor for atherosclerotic CVD, but other data, including clinical trial data, have been interpreted to suggest that elevated TG may just be a marker, rather than an independent risk factor for CVD. This is because of the interrelationship of TG with other lipids such as low levels of high-density lipoprotein cholesterol (HDL-C) and increased levels of small, dense LDL-C particles. In more recent times, elevated TG have been felt to reflect the presence of TG in atherogenic TG-rich lipoprotein remnants (TRLR) consisting of chylomicron remnants and very-low-density lipoprotein (VLDL) remnant particles [6]. These TRLR appear to generate toxic substances and damage the endothelium when they come into contact with endothelial lipoprotein lipase (LPL) [7]. A recent prospective study demonstrated that fasting TG > 150 mg/dl were predictive of future events in patients with known coronary artery disease (CAD) [8], and reports of patients with apolipoprotein CIII (apoCIII) mutations, which result in chronically low TG (and apoCIII) levels, have correlated with significantly decreased risk of CVD [9,10]. Outcome data are lacking in this area, and previous clinical trials looking at outcomes had inadequate experimental designs [11]. More recent reviews focus on the potential polygenic nature of hypertriglyceridemia and relationship of TG to CVD [12-14]. Hypertriglyceridemia in the United States According to the most recent AHA scientific statement on triglycerides and CVD [6], 31% of the US adult population has a TG level ‡ 150 mg/dl. Data suggest that the prevalence of hypertriglyceridemia is related to obesity as shown by body mass index (BMI) [15]. There have only been slight increases in median TG levels over time based on the National Health 1.3
124
and Nutrition Examination Survey (NHANES) data from 1988 to 1994 and 1999 to 2008. TG levels are not normally distributed in the population and are usually expressed by the median value to decrease the effect of outliers. There were small increases in median TG levels in both men (122 vs 119 mg/dl) and women (106 vs 101 mg/dl) noted in the previously cited NHANES data. The increases in TG primarily were observed in the 20- to 49-year-old age group, which most likely is a reflection of the increasing incidence of obesity and diabetes in childhood and adolescence [16]. 2.
Body of review
Overview of the market Elevated TG have traditionally been very difficult to treat adequately. Currently niacin, fibrates, or w3 fatty acids can be used to treat elevated TG and are often used concomitantly with statins and lifestyle modifications. Niacin safety and benefit have both been questioned based on relatively recent clinical trials. The AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) compared statin with statin plus extended-release niacin in 3414 subjects [17]. After 3 years, there was no benefit in the niacin group, but there was an increase in stroke in the niacin group, although not statistically significant. In the HPS2-THRIVE trial (Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events), statin was compared with statin plus niacin and laropiprant (an anti-flushing agent) in 25,673 subjects. Again, addition of niacin did not appear to have any outcome benefit but had increased incidence of serious adverse events (AE) but not an increase in stroke [18]. Additionally, niacin may be difficult to tolerate in the long term at the doses necessary to affect lipid lowering. Niacin is also contraindicated in liver disease and should be used cautiously in diabetes. The most commonly used fibrates are fenofibrate and gemfibrozil. Gemfibrozil has fallen out of favor in clinical use because of its effect on statin metabolism by inhibiting glucuronidation, resulting in increased risk of myopathy [19]. Fenofibrate showed no outcomes benefit when combined with statin in 5518 patients with type 2 diabetes mellitus in the ACCORD (The Action to Control Cardiovascular Risk in Diabetes) trial [20]. Fibrate use is also associated with increased gallstones and creatinine levels. It should be noted that post hoc analyses of several fibrate trials have shown cardiovascular benefit in a subgroup of patients with low HDL-C and high TG levels, but these findings are hypothesis-generating and not conclusive. w3 fatty acids are mainly composed of long-chain w3 fatty acids, including eicosapentaenoic acid (EPA) (C20:5n-3) and docosahexaenoic acid (DHA) (C22:6n-3) (Figure 1). These are obtained from fish oil and are not available from plant sources in any significant quantity. There are currently several prescription and multiple over-the-counter fish oil preparations. 2.1
Expert Opin. Pharmacother. (2015) 16(1)
w-3 carboxylic acids
Table 1. Triglyceride categories by ATP2 and ATP3. Triglyceride category
ATP II level (mg/dl)
ATP III level (mg/dl)
ATP II level (mmol/l)
ATP III level (mmol/l)
Normal Borderline-high High Very high
< 200 200 -- 399 400 -- 1000 > 1000
< 150 150 -- 199 200 -- 499 ‡ 500
< 2.26 2.26 -- 4.50 4.51 -- 11.29 > 11.29
< 1.69 1.69 -- 2.25 2.26 -- 5.63 ‡ 5.64
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ATP: Adult treatment panel.
O HO
EPA CA (FFA) O HO
DHA CA (FFA) O
H 5O EPA EE O C2H5O DHA EE
Figure 1. Structures of v3 EE and v3 CA (FFA). CA: Carboxylic acid; DHA: Docosahexaenoic acid; EE: Ethyl ester; EPA: Eicosapentaenoic acid; FFA: Free fatty acid.
The benefit of the prescription fish oils is a higher percent of OM3 per 1 g capsule and a usually greater degree of purification compared to over-the-counter preparations, resulting in less fishy taste and gastrointestinal (GI) symptoms. w3 compounds have a long safety history and are considered quite safe. Efficacy of w3 preparations is dependent on the dose utilized and the degree of hypertriglyceridemia. The maximum TG-lowering effect is seen with approximately 4 g of w3 preparations, and the greater the TG level, the greater the percent reduction of TG. w3 preparations in adequate doses generally decrease TG by 25 -- 30%. Three branded w3 capsules approved in the US are Lovaza (GlaxoSmithKline, Research Triangle Park, NC, USA), Vascepa (Amarin Pharma, Inc. Bedminster, NJ, USA) and
Omtryg (Trygg Pharmaceuticals, Oslo, Norway). Lovaza and Omtryg both contain w3 ethyl esters (w3 EE) of EPA and DHA. Vascepa is an w3 EE containing only EPA. A generic w3 EE equivalent to Lovaza has been introduced by Teva Pharmaceuticals (Petach Tikva, Israel) [21-24]. Epanova is FDA approved in the US but not yet marketed at the time of writing this article. A comparison of the lipid lowering effects of Epanova, Lovaza and Vascepa in severe hypertriglyceridemia without correction for placebo or control effect can be found in Table 2. Introduction to the compound w3 carboxylic acids (w3 CA) also called w3 free fatty acids (w3 FFA) (Box 1) are EPA and DHA in the FFA form versus 2.2
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Table 2. Comparison of Epanova with Lovaza and Vascepa.
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v3 dose
Epanova 2 g/d
Epanova 4 g/d
Lovaza 4 g/d
Vascepa 4 g/d
n = 100
n = 99
n = 42
n = 76
Parameter
BL
% Change
BL
% Change
BL
% Change
BL
% Change
TG Non-HDL-C TC VLDL-C HDL-C LDL-C ApoB
717 205 241 123 27 77 114
--25 --8 --6 --25 +7 +21 +6
655 225 254 126 29 90 118
--31 --8 --6 --35 +5 +26 +6
816 271 296 175 22 89 --
--44.9 --13.8 --9.7 --41.7 +9.1 +44.5 --
680 225 254 123 27 91 121
--27 --8 --7 --20 --4 --5 --4
% change values are not corrected for placebo or control results. Data modified from product information accessed online 1NOV2014. ApoB: Apolipoprotein B; BL: Baseline in mg/dl; g/d: g/day; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; N: Number; Non-HDL-C: Non-high-density lipoprotein cholesterol; TC: Total cholesterol; TG: Triglycerides; VLDL-C: Very-low-density lipoprotein cholesterol.
other available w3 preparations that can be considered prodrugs containing w3 EEs. w3 CA undergoes an additional step during the manufacturing process that hydrolyzes the w3 EE into w3 CA, which is readily absorbed in the GI tract. Transport across the intestinal wall is dependent on fat being in the FFA form. It is re-esterified within the intestinal cell for transport as a TG. In contrast, w3 EE, once consumed, needs to be hydrolyzed into the FFA form by carboxyl ester lipase, also called bile salt-dependent lipase. The carboxyl ester lipase is a pancreatic enzyme secreted when stimulated by ingestion of fat and is therefore meal dependent [25]. Chemistry Each gram of w3 CA contains at least 850 mg of polyunsaturated fatty acids, including multiple w3 fatty acids, with EPA and DHA being the most abundant [26]. Compared with the w3 EE Lovaza, w3 CA contains 75% EPA and DHA and w3 EE contains 84% EPA and DHA. Because the w3 EE has to undergo hydrolysis to be absorbed and w3 CA does not, approximately the same amount of EPA and DHA are available for absorption after hydrolysis of the w3 EE assuming complete hydrolysis of the w3 EE occurs [27]. 2.3
Pharmacodynamics Review of the literature concerning the TG-lowering mechanism of action of w3 compounds reveals gaps in our knowledge base. There is agreement that w3s decrease the hepatic synthesis of VLDL, increase b-oxidation of fatty acids, thus decreasing their availability for TG synthesis, and enhance the clearance of TG from VLDL and chylomicron particles by increasing LPL activity [28]. The result of these changes is a reduction in TG, VLDL and non-HDL-C, sometimes accompanied by an increase in LDL-C thought to be due to increased cholesterol content of LDL particles, not increased numbers of atherogenic apolipoprotein B (apoB) containing particles [29-31]. 2.4
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Pharmacokinetics and metabolism After oral administration, w3 CA is directly absorbed in the small intestine, eventually entering the lymphatic system and the thoracic duct, and emptying into the superior vena cava. Maximum EPA plasma concentrations are achieved 5 -- 8 h after dosing with 4 g of w3 CA with low-fat meal conditions after repeat daily dosing for 2 weeks. Maximum DHA concentration is achieved under the same conditions in 5 -- 9 h. Steady-state concentrations of EPA and DHA are achieved within 2 weeks of repeat daily dosing. The EPA and DHA are distributed in phospholipids, TG and cholesterol esters. Metabolism of w3 CA is by oxidation in the liver similar to other fatty acids from the diet. Following repeat dosing, the half-life of EPA and DHA from w3 CA is 37 and 46 h, respectively. There is no renal excretion [26]. 2.5
3.
Clinical efficacy
Pharmacokinetic studies Originally, w3 CA underwent clinical trials as a treatment for Crohn’s disease but were not successful in preventing disease flares. The safety of the preparation was shown during those trials [32]. There have been four clinical trials with the w-3 CA, two focusing on TG lowering and two PK studies. These include two trials looking at pharmacokinetics and bioavailability of w-3 CA as both single dose and multiple dosing and two studies investigating clinical efficacy in two different fasting TG level populations. The ECLIPSE trial (Epanova compared to Lovaza in a pharmacokinetic single-dose evaluation trial) was a bioavailability four-way crossover study in 54 obese but otherwise healthy adults [27]. The purpose was to compare bioavailability of w3 CA to w3 EE during both low and high-fat meals. Each dosing period consisted of a 24-h collection of PK data analyzing EPA and DHA levels after a single 4-g dose of either w3 CA or w3 EE followed by either low- or high-fat meals for the entire day. The dose was taken either in the fasted state 3.1
Expert Opin. Pharmacother. (2015) 16(1)
Total EPA+DHA plasma concentrations (nmol/ml)
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w-3 carboxylic acids
400
Test: ω3 FFA, low-fat diet Reference: ω3 EE, low-fat diet
350 300 250 200 150 100 50 0 0
2
4
6
8
10
12
14
16
18
20
22
24
Time (h)
Figure 2. ECLIPSE low-fat diet -- total EPA + DHA plasma concentration. Mean (SD) total EPA + DHA concentration time profiles (baseline-adjusted change) after a single 4 g dose of w3 FFA (CA) vs w3 EE during the low-fat period. Reproduced with permission from [27]. DHA: Docosahexaenoic acid; EE: Ethyl ester; EPA: Eicosapentaenoic acid; FFA: Free fatty acid.
followed by low-fat meals throughout the 24 h PK period (low-fat period) or 30 min following a high-fat meal followed by high-fat meals throughout the 24 h PK period (high-fat period). A minimum of a 1-week washout occurred between dosing periods during which all subjects followed a Therapeutic Lifestyle Changes (TLC) diet. The AUC of the total EPA + DHA plasma concentrations versus time were fourfold higher for w3 CA vs w3 EE during the low-fat meal period (Figure 2) and 1.3-fold higher during the high-fat meal period. The conclusion was that w3 CA has increased bioavailability over w3 EE in the low-fat state, making it a viable option for use when patients follow a low-fat diet typically prescribed for hypertriglyceridemia. The ECLIPSE II trial was a 2-week multiple-dose PK study of 4 g of w3 CA versus w3 EE in 52 healthy subjects on lowfat diets, as high-risk cardiovascular patients are advised to follow a low-fat diet [33]. The w3 was dosed daily for 14 consecutive days, and levels of combined EPA and DHA were obtained. The baseline levels between the two groups after 7 days of the TLC diet were essentially equal. At 14 days, the w3 CA had a threefold greater EPA + DHA serum concentration than the w3 EE. Phase III studies The EVOLVE trial (The Epanova for lowering very high triglycerides) randomized 399 patients with TG between 500 and < 2000 mg/dl to either 4 g/day (g/d) of olive oil (OO) as control, 2 g/d of w3 CA and 2 g/d of OO, 3 g/d of w3 CA and 1 g/d of OO or 4 g/d of w3 CA. The study was 3.2
12 weeks in length and a double-blind, international, randomized, parallel group design [29]. The baseline demographics of the four treatment groups were similar. TG were lowered 4.3, 25.9, 25.5 and 30.9% by control (4 g/d OO), 2 g/d w3 CA (+2 g/d OO), 3 g/d w3 CA (+1 g/d OO) and 4 g/d w3 CA, respectively (all values % least squares geometric mean). All of the lipoprotein and biomarker results can be seen in Table 3. As has been seen with other lipid-lowering agents, the higher the baseline TG value, the greater the reduction in TG level. In addition to TG being lowered, other apparent favorable changes occurred in non-HDL-C, VLDL-C, remnant-like particle cholesterol (RLP-C) and apoCIII. The LDL-C, corrected for control changes, increased by 19% in the 2 and 4 g/d w3 CA arms, but apoB only increased 3.8%, which was not statistically different than the placebo arm. This suggests that the increase in LDL-C is due to increased cholesterol content of the LDL particles, not an increase in particle number, and thus is not likely to mean increased atherogenic potential. Treatment-emergent AEs (TEAEs) occurring in > 3% of patients are shown in Table 4. The TEAEs that appear related to w3 CA are overall GI complaints and more specifically diarrhea and nausea as well as eructation. The ESPRIT trial (A highly bioavailable w3 FFA formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia) was a double-blind, parallel-group study in 647 patients on statin therapy with fasting TG levels of ‡ 200 and < 500 mg/dl [34]. Patients were at high risk for CVD and on maximally tolerated statin or statin with ezetimibe prior to randomization.
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Table 3. EVOLVE trial partial lipid results (modified intent-to-treat population).
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Variable
TG, mg/dl Baseline EOT % D LSGM (95% CI) Non-HDL-C, mg/dl Baseline EOT % D LSGM (95% CI) HDL-C, mg/dl Baseline EOT % D LSGM (95% CI) Total C, mg/dl Baseline EOT % D LSGM (95% CI) LDL-C, mg/dl Baseline EOT % D LSGM (95% CI) VLDL-C, mg/dl Baseline EOT % D LSGM (95% CI) RLP-C, mg/dl Baseline EOT % D LSGM (95% CI) Apo B, mg/dl Baseline EOT % D LSGM (95% CI) Apo CIII, mg/dl Baseline EOT % D LSGM (95% CI)
Control, OO 4g/d n = 98
v3 CA 2 g/d n = 99
v3 CA 3 g/d n = 97
v3 CA 4 g/d n = 99
682 642 -4.3 (-13.1 to 5.4)
717 554 -25.9z (-32.8 to -18.1)
728 544 -25.5z (-32.4 to -17.8)
655 513 -30.9§ (-37.3 to -23.7)
215 217 2.5 (-2.3 to 7.6)
205 209 -7.6* (-12.0 to -3.0)
215 197 -6.9* (-11.4 to -2.2)
225 211 -9.6z (-14.0 to -5.1)
28.7 30.0 1.9 (-2.0 to 6.0)
27.3 29.0 7.4 (3.2 to 11.7)
28.0 28.5 3.8 (-0.3 to 8.0)
28.7 29.0 5.8 (1.7 to 10.1)
246 244 3.2 (-1.0 to 7.5)
241 233 -5.4* (-9.3 to -1.4)
244 228 -4.9 (-8.7 to -0.8)
254 247 -7.5z (-11.2 to -3.5)
78.2 86.3 3.0 (-2.9 to 9.3)
77.3 93.3 19.2z (12.3 to 26.5)
81.0 95.0 14.3 (7.6 to 21.4)
90.3 110 19.4§ (12.4 to 26.8)
125 113 -8.5 (-16.6 to 0.3)
123 98.0 -26.6z (-33.1 to -19.4)
124 92.8 -26.4z (-33.0 to -19.2)
126 87.0 -33.0§ (-39.0 to -26.4)
52.3 41.0 3.4 (-10.1 to 18.9)
44.5 37.0 -20.7* (-30.9 to -8.9)
42.5 34.5 -22.6* (-33.1 to -10.6)
43.0 33.0 -27.5§ (-36.9 to -16.7)
110 116 0.9 (-3.6 to 5.5)
114 120 3.8 (-0.7 to 8.5)
112 115 2.3 (-2.4 to 7.2)
118 122 3.8 (-0.8 to 8.5)
24.0 26.0 1.6 (-5.0 to 8.6)
24.5 21.0 -10.9* (-16.6 to -4.8)
26.0 21.0 -12.2z (-18.0 to -5.9)
24.5 21.0 -14.4§ (-19.9 to -8.5)
Adopted from [29]. *Significantly different from the OO group, p < 0.05. z Significantly different from the OO group, p < 0.01. § Significantly different from the OO group, p < 0.001. % D LSGM: Percent change by least square geometric mean; Apo B: Apolipoprotein B; apo CIII: Apolipoprotein CIII; C: Cholesterol; CA: Carboxylic acid; EOT: End of treatment; g/d: g/day; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; n: Number; OO: Olive oil; RLP: Remnant-like particle; TG: Triglycerides; VLDL: Very-low-density lipoprotein.
They were randomized to placebo 4 g/d (OO), 2 g/d w3 CA (+2 g/d OO) or 4 g/d of w3 CA and treated for 6 weeks. The primary objective was to evaluate the efficacy of adding 2 or 4 g/d of w3 CA to hypertriglyceridemic patients on statin 128
to see the effect on non-HDL-C and TG after a 6-week diet and statin stabilization period. TG were reduced by 5.9, 14.6 and 20.6% for OO, w3 CA 2 g/d and w3 CA 4 g/d, respectively. Compared with OO, changes in TG by both doses of
Expert Opin. Pharmacother. (2015) 16(1)
w-3 carboxylic acids
Table 4. EVOLVE Study TEAEs occurring in > 3% of subjects in safety population.
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System
Gastrointestinal All Upper abd pain Diarrhea Eructation Nausea Vomiting Infections All Nasopharyngitis Metabolism and Nutrition disorders Musculoskeletal disorders Nervous system disorders Skin disorders
Control OO 4 g/d n = 99
v3 CA 2 g/d n = 100
v3 CA 3 g/d n = 101
v3 CA 4 g/d n = 99
7 1 2 1 1 1
(7.1) (1.0) (2.0) (1.0) (1.0) (1.0)
19 (19.0) 4 (4.0) 10 (10.0) 3 (3.0) 6 (6.0) 2 (2.0)
21 (20.8) 1 (1.0) 6 (5.9) 4 (4.0) 9 (8.9) 4 (4.0)
27 (27.3) 1 (1.0) 10 (10.1) 4 (4.0) 5 (5.1) 0 (0.0)
11 (11.1) 2 (2.0)
14 (14.0) 7 (7.0)
7 (6.9) 3 (3.0)
12 (12.1) 1 (1.0)
2 (2.0)
0 (0.0)
1 (1.0)
4 (4.0)
6 (6.1) 0 (0.0) 0 (0.0)
5 (5.0) 6 (6.0) 4 (4.0)
6 (5.9) 5 (5.0) 1 (1.0)
3 (3.0) 4 (4.0) 2 (2.0)
Values are given as number (percent). Adopted from [29] with permission. Abd: Abdominal; CA: Carboxylic acid; g/d: g/day; OO: Olive oil; n: Number; TEAE: Treatment emergent adverse event.
w3 CA were statistically significant (p < 0.001). Non-HDL-C was reduced by 0.9, 3.9 and 6.9% for OO, w3 CA 2 g/d and w3 CA 4 g/d, respectively. Compared with OO, 2 g/d w3 CA significantly reduced non-HDL-C (p < 0.05), as did the 4 g/d dose (p < 0.0001). See Table 5 for additional results. Safety data related to TEAEs occurring in > 3% of patients are shown in Table 6. Similar to the EVOLVE trial, the only TEAEs that appear related to w3 CA are overall GI complaints and more specifically diarrhea and nausea, all of which were reported as transient and mild.
Post-marketing surveillance (cardiovascular outcomes trials)
3.3
A large Phase III outcomes trial is planned for w3 CA. The study is entitled ‘A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction with EpaNova in HiGh Cardiovascular Risk PatienTs with Hypertriglyceridemia’ (STRENGTH) [35]. Thirteen thousand high CVD risk patients on statin (+/- ezetimibe) therapy with TG ‡ 200 and < 500 mg/ dl and HDL < 40 mg/dl in men or HDL < 45 mg/dl in women will be randomized 1:1 to w3 CA 4 g/d versus control (corn oil) 4 g/d. The study will continue for ~ 3 -- 5 years until 1600 primary events are accrued. Results are expected in 2019. An additional outcomes trial for w3 EE containing EPA only (Vascepa) is currently under way and expected to have results by the end of 2016. The study is called REDUCE-IT and is ‘A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients with Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/d AMR101 for Preventing the Occurrence of a First Major
Cardiovascular Event.’ It will enroll 8000 high-risk patients and tests 4 g/d of EPA w3 EE against placebo (mineral oil) [36]. 4.
Safety and tolerability
w3 compounds have a long history of use and are generally considered safe. In 1997, the FDA concluded that total intakes (from diet and supplements) of EPA and DHA up to 3 g/d were generally recognized as safe (GRAS) and approved a prescription w3 medication at 4 g/d in 2004. The potential major AEs associated with w3 use are increased bleeding, impaired immune function and impaired glucose metabolism. In 2012, the European Food Safety authority (EFSA) reviewed the available w3 information and concluded that DHA plus EPA usage up to 5 g/d (or EPA alone up to 1.8 g/d) did not have any safety concerns for adults [37]. The minor AEs associated with w3 are GI symptoms of eructation, nausea and diarrhea or loose stools. Safety data from the w3 CA trials appear favorable with low rates of moderate or severe AEs. A summary of the safety data from the two Phase III TG lowering w3 CA studies is below. EVOLVE treatment emergent AEs (TEAEs) occurring in > 3% of patients are shown in Table 4. The only TEAEs that appear related to w3 CA are overall GI complaints and more specifically diarrhea and nausea as well as perhaps eructation. The majority of AEs were considered mild. ESPRIT safety data related to TEAEs occurring in > 3% of patients are shown in Table 6. Similar to the EVOLVE trial, the only TEAEs that appear related to w3 CA are overall GI complaints and more specifically diarrhea and nausea, all of which were reported as transient and mild.
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E. M. Roth
Table 5. ESPIRIT study results.
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Variable TG, mg/dl Baseline EOT % D LSGM (95% CI) Non-HDL-C, mg/dl Baseline EOT % D LSGM (95% CI) HDL-C, mg/dl Baseline EOT % D LSGM (95% CI) Total C, mg/dl Baseline EOT % = LSGM (95% CI) LDL-C, mg/dl Baseline EOT % D LSGM (95% CI) VLDL-C, mg/dl Baseline EOT % D LSGM (95% CI) RLP-C, mg/dl Baseline EOT % D LSGM (95% CI) Apo B, mg/dl Baseline EOT % D LSGM (95% CI) Apo CIII, mg/dl Baseline EOT % D LSGM (95% CI)
Statin + control OO 4g/d n = 211
Statin + v3 CA 2 g/d n = 209
Statin + v3 CA 4 g/d n = 207
280 268 -5.9 na
284 244 -14.6§ na
287 233 -20.6§ na
135 136 -0.9 na
140 136 -3.9* na
139 132 -6.9§ na
38.8 39.8 2.2 na
38.7 39.8 2.6 na
38.8 40.3 3.3 na
174 176 0.5 (-1.2 to 2.2)
179 176 -1.71 (-3.4 to -0.0)
178 172 -3.83§ (-5.4 to -2.1)
91.7 92.8 1.1 (-1.6 to 3.8)
92.3 96.6 4.6* (1.8 to 7.4)
93.6 94.2 1.3 (-1.4 to 4.1)
45.7 43.6 -5.9 (-10.4 to -1.1)
46.9 39.8 -14.3z (-18.4 to -10.0)
47.2 37.5 -21.5§ (-25.2 to -17.5)
52.3 41.0 3.4 (-10.1 to 18.9)
44.5 37.0 -20.7 (-30.9 to -8.9)
42.5 34.5 -22.6 (-33.1 to -10.6)
93.8 94.4 0.3 (-1.6 to 2.2)
94.5 95.6 0.7 (-1.2 to 2.6)
95.9 93.8 -2.1* (-4.0 to -0.3)
24.0 26.0 1.6 (-5.0 to 8.6)
24.5 21.0 -10.9 (-16.6 to -4.8)
26.0 21.0 -12.2 (-18.0 to -5.9)
Adopted from [34] with permission. *Significantly different from the OO group, p < 0.05. z Significantly different from the OO group, p < 0.01. § Significantly different from the OO group, p < 0.001. % D LSGM: Percent change by least square geometric mean; Apo B: Apolipoprotein B, apo CIII: Apolipoprotein CIII; C: Cholesterol; CA: Carboxylic acid; EOT: End of treatment; g/d: g/day; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; n: Number; Na: Not available; OO: Olive oil; RLP: Remnant-like particle; TG:Triglycerides; VLDL: Very-low-density lipoprotein.
5.
Regulatory affairs
w3 CA (Epanova) was approved by the US FDA in May 2014 for use in patients with TG ‡ 500 mg/dl as an adjunct 130
to diet therapy. As of November 2014, Epanova was not yet available on the market for prescribing. Omthera Pharmaceuticals (Princeton, NJ, USA) is now owned by AstraZeneca (London, UK).
Expert Opin. Pharmacother. (2015) 16(1)
w-3 carboxylic acids
Table 6. ESPRIT Study TEAEs occurring in > 3% of subjects in safety population. Values are given as number (percent).
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System
Gastrointestinal All Diarrhea Nausea Infections All Musculoskeletal disorders Nervous system disorders
Statin + control OO 4 g/d n = 215
Statin + v3 CA 2 g/d n = 215
Statin + v3 CA 4 g/d n = 216
19 (8.8) 5 (2.3) 3 (1.4)
29 (13.5) 13 (6.0) 6 (2.8)
58 (26.9) 36 (16.7) 13 (6.8)
21 (9.8) 11 (5.1) 3 (1.4)
7 (3.3) 7 (3.3) 2 (0.9)
17 (7.9) 10 (4.6) 8 (3.7)
Adopted from [34] with permission. CA: Carboxylic acid; g/d: g/day; n: Number; OO: Olive oil; TEAE: Treatment emergent adverse event.
6.
Conclusion
w3 CA appears safe and effective for lowering TG. There are potential advantages to the CA (FFA) form due to increased absorption from the GI tract without dependence on pancreatic enzymes, which are triggered by meals, especially high-fat meals. In addition to TG lowering, non-HDL-C, total cholesterol and apoCIII are also decreased. LDL-C is increased, but apoB is not significantly increased, suggesting an increase in cholesterol content of LDL particles, without a significant increase in atherogenic particle numbers. This can change the more atherogenic small, dense LDL particles into less atherogenic larger LDL particles as well as decrease the number of TG- rich remnants that are in the circulation. All of these changes should lead to a decrease in atherosclerosis, which could potentially result in decreased CV events. 7.
Expert opinion
w3 CA is a newly available source of prescription w3 fish oil that is significantly less dependent on concomitant food intake than other currently available w3 products. The other w3 products are w3 EEs that require pancreatic enzymes for breakdown in the gut before absorption by the small bowel. w3 EEs are best absorbed with a high-fat meal, which is contraindicated in patients with hypertriglyceridemia. w3 CA is readily absorbed in the small intestine without the need for pancreatic enzymatic action and w3 CA has 3 -- 4 times the bioavailability compared to w3 EE in low-fat meal situations. The lower 2 g/d dose of w3 CA has been shown to reduce triglycerides by 25%, which was a significant reduction. This lower dose may offer better patient compliance and adherence to therapy because of less capsules per day, less need to take with meals and perhaps fewer AEs then the 4 g dose. These same factors may be an inducement for physicians to prescribe the w3 CA over the w3 EE preparations. w3 CA at 2 and 4 g/d appears to have similar lipid effects as the EPA EE preparation on TG and non-HDL-C but an increase in LDL-C
(with minimal increase in apoB) versus a slight decline in LDL-C and apoB for EPA EE. With potent statins and newer classes of LDL-C lowering drugs, this may not be a significant difference factor. The combination EPA and DHA EE preparation shows a better effect on decreasing TG and non-HDL-C then w3 CA but a 44% increase in LDL-C, which may be significant. The major question that needs answering is whether w3 preparations used with statin therapy will be beneficial to the patient and decrease the incidence of CVD. The clinical trial post hoc data, genomic data and population studies suggest that if the LDL-C is controlled and TG are increased (> 200 mg/dl for now), there should be additional cardiovascular benefit to lowering TG. The two large well-designed outcomes trials previously described should help answer this question in the next several years. I believe that lowering elevated TG (perhaps > 150 mg/dl or even lower) will have CV benefit and will be shown with a clinical trial that is properly designed and carried out. Combination therapy with w3 CA and a statin may be the combination of choice in the future if clinical trial results show benefit to lowering TG. The attractiveness of a combination statin/w3 compound is the lack of interaction between the two and the low AE profile of the w3 in comparison to previous combinations of statin and fibrate or niacin. Also, patients are more accepting of an w3 preparation because they consider it a natural substance and this may contribute to initial acceptance and long-term adherence. There is still a significant residual risk of CVD despite adequate LDL-C lowering with statins, hopefully the addition of w3 medications to lower TG will have a significant effect on reducing that residual risk. We anxiously await the results of the two w3 outcomes trials.
Acknowledgement The author thanks Kevin C Maki, PhD for kindly reviewing the manuscript and making editorial suggestions.
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Declaration of interest EM Roth has received speakers bureau for AstraZeneca. The author has no other relevant affiliations or financial Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
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Werner C, Filmer A, Fritsch M, et al. Risk prediction with triglycerides in patients with stable coronary disease on statin treatment. Clin Res Cardiol 2014;103(12):984-97 Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease. The TG and HDL working group of the exome sequencing project, national heart, lung, and blood institute. N Engl J Med 2014;371:22-31 Review of TG and ApoCIII relationship.
Effects of extended-release niacin with laropiprant in high-risk patients: the HPS2-THRIVE collaborative group. N Engl J Med 2014;371:203-12
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Prueksaritanont T, Zhao JJ, Ma B, et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther 2002;301(3):1042-51
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Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. The ACCORD Study Group N Engl J Med 2010;362:1563-74
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Chapman MJ, Ginsberg HN, Amarenco P, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61 Comprehensive review of TG and European recommendations.
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Goldberg IJ, Eckel RH, McPherson R. Triglycerides and heart disease: still a hypothesis? Arterioscler Thromb Vasc Biol 2011;31:1716-25
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Sarwar N, Sandhu MS, Ricketts SL, et al. Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 2010;375:1634-9
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Nordestgaard BG, Varbo A; Lipids and cardiovascular disease 3. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35
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Hegele RA, Ginsberg HN, Chapman MJ. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2014;2(8):655-66
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Kromhout D, de Goede J. Update on cardiometabolic health effects of w-3 fatty acids. Curr Opin Lipidol 2014;25:85-90
Hui DY, Howles PN. Carboxyl ester lipase: structure-function relationship and physiological role in lipoprotein metabolism and atherosclerosis. J Lipid Res 2002;43(12):2017-13
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Davidson MH, Johnson J, Rooney MW, et al. A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova compared to Lovaza in a pharmacokinetic single-dose evaluation) study. J Clin Lipidol 2012;6:573-84 Review of v-3 CA versus v -3 EE.
Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013;ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63(25 Pt B):2889-934 Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292-333 Comprehensive review of TG and CVD. Wang L, Gill R, Pedersen TL, et al. Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that
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Offman E, Marenco T, Ferber S, et al. Steady-state bioavailability of prescription omega-3 on a low-fat diet is significantly improved with a free fatty acid formulation compared with an ethyl ester formulation: the ECLIPSE II study. Vasc Health Risk Manag 2013;9:563-73 Maki KC, Orloff DG, Nicholls SJ, et al. A highly bio available omega 3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT Trial). Clin Ther 2013;35(9):1400-11 Available from: http://clinicaltrials.gov/ show/NCT02104817 [Accessed 14 September 2014]
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Affiliation Eli M Roth MD FACC FNLA Professor, Cardiology University of Cincinnati, Sterling Research Group, 375 Glensprings Dr. 2nd Floor, Cincinnati, OH 45246 USA Tel: +1 513 671 8080; Fax: +1 513 671 8090 E-mail: [email protected]
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v-3 carboxylic acids for hypertriglyceridemia
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Eli M Roth University of Cincinnati & Sterling Research Group, Cincinnati, OH, USA
1.
Introduction
2.
Body of review
3.
Clinical efficacy
4.
Safety and tolerability
5.
Regulatory affairs
6.
Conclusion
7.
Expert opinion
Introduction: w-3 carboxylic acids (w3 CA), also called w3 free fatty acids (w3 FFA), with the trade name Epanova is a new formulation of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) approved for the treatment of severe hypertriglyceridemia. The FFA form of EPA and DHA is associated with higher bioavailability than other forms of w3 fatty acids, potentially resulting in efficacy at lower doses and less dependence on meal relationship. Areas covered: The efficacy and safety of w3 CA from clinical trials as well as PK and PD data will be reviewed. The mechanism of action of w3 fatty acids in the lowering of triglycerides (TG) will be discussed and comparison is made with w3 ethyl ester compounds. Expert opinion: w3 CA are a unique form of w3 fatty acids that appear safe and effective in lowering serum TG and offer the possibility of better patient compliance due to lower-dose efficacy and the ability to take with or without food. w3 CA lowered TG by 26 and 31% for the 2 and 4 g/day doses, respectively, and Apo CIII was also lowered 11 and 14%, respectively, as well. Keywords: DHA, EPA, Epanova, fish oil, w-3, w-3 carboxylic acids, w-3 free fatty acids, triglycerides Expert Opin. Pharmacother. (2015) 16(1):123-133
1.
Introduction
Hypertriglyceridemia and v-3 compounds Hypertriglyceridemia is increasing in the US and throughout the world, with an estimated prevalence of four million Americans meeting the definition of severe hypertriglyceridemia (‡ 500 mg/dl) [1]. The US FDA approves the use of prescription w-3 compounds to lower triglyceride (TG) only for very high levels (‡ 500 mg/ dl) but notes the effect on the risk of pancreatitis or morbidity or mortality of cardiovascular disease (CVD) has not been determined. Although severe hypertriglyceridemia appears to be a causal factor for acute pancreatitis, there has never been a clinical study performed to show that lowering TG is beneficial. The ATP III guidelines recommended that once low-density lipoprotein cholesterol (LDL-C) level was at target, that a TG ‡ 200 mg/dl should be treated [2]. The guidelines from the European Society of Cardiology state that CVD risk is increased if fasting TG are ‡ 1.7 mmol/l (‡ 150 mg/dl), but that drugs to lower TG should only be considered if TG is ‡ 2.3 mmol/l (‡ 200 mg/dl) and the patient is at high CVD risk and cannot lower their TG by lifestyle measures [3,4]. 1.1
Hypertriglyceridemia and CVD The last official US guideline to deal with the definition of hypertriglyceridemia was the National Cholesterol Education Program -- Adult Treatment Panel III (NCEP ATPIII) in 2001, which defined normal TG level as < 150 mg/dl, borderline high as 150 -- 199 mg/dl, high as 200 -- 499 mg/dl and very high TG as ‡ 500 mg/dl [2]. The ATP III TG definitions were considerably lower than the previous ATP II TG levels (Table 1). The 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines on the Treatment of Blood Cholesterol to 1.2
10.1517/14656566.2015.991307 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name
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Phase Indication Pharmacology description
Route of administration Chemical structure
Trials
w-3 carboxylic acid (w3 CA) or w-3 free fatty acid (w3 FFA) Approved in the US Hypertriglyceridemia (‡ 500 mg/dl) w3s decrease the hepatic synthesis of VLDL, increase beta oxidation of fatty acids thus decreasing their availability for TG synthesis, and enhance the clearance of TG from VLDL particles and chylomicrons by increasing LPL activity Oral Eicosapentaenoic acid (EPA) (C20:5n-3) and docosahexaenoic acid (DHA) (C22:6n-3) ECLIPSE, ECLIPSE II, EVOLVE, ESPRIT
Reduce Atherosclerotic Cardiovascular Risk in Adults (formerly ATP IV) did not deal with TG, as the panel felt that good data were lacking to make recommendations [5]. Epidemiologic data have long supported the concept that an elevated TG level is a risk factor for atherosclerotic CVD, but other data, including clinical trial data, have been interpreted to suggest that elevated TG may just be a marker, rather than an independent risk factor for CVD. This is because of the interrelationship of TG with other lipids such as low levels of high-density lipoprotein cholesterol (HDL-C) and increased levels of small, dense LDL-C particles. In more recent times, elevated TG have been felt to reflect the presence of TG in atherogenic TG-rich lipoprotein remnants (TRLR) consisting of chylomicron remnants and very-low-density lipoprotein (VLDL) remnant particles [6]. These TRLR appear to generate toxic substances and damage the endothelium when they come into contact with endothelial lipoprotein lipase (LPL) [7]. A recent prospective study demonstrated that fasting TG > 150 mg/dl were predictive of future events in patients with known coronary artery disease (CAD) [8], and reports of patients with apolipoprotein CIII (apoCIII) mutations, which result in chronically low TG (and apoCIII) levels, have correlated with significantly decreased risk of CVD [9,10]. Outcome data are lacking in this area, and previous clinical trials looking at outcomes had inadequate experimental designs [11]. More recent reviews focus on the potential polygenic nature of hypertriglyceridemia and relationship of TG to CVD [12-14]. Hypertriglyceridemia in the United States According to the most recent AHA scientific statement on triglycerides and CVD [6], 31% of the US adult population has a TG level ‡ 150 mg/dl. Data suggest that the prevalence of hypertriglyceridemia is related to obesity as shown by body mass index (BMI) [15]. There have only been slight increases in median TG levels over time based on the National Health 1.3
124
and Nutrition Examination Survey (NHANES) data from 1988 to 1994 and 1999 to 2008. TG levels are not normally distributed in the population and are usually expressed by the median value to decrease the effect of outliers. There were small increases in median TG levels in both men (122 vs 119 mg/dl) and women (106 vs 101 mg/dl) noted in the previously cited NHANES data. The increases in TG primarily were observed in the 20- to 49-year-old age group, which most likely is a reflection of the increasing incidence of obesity and diabetes in childhood and adolescence [16]. 2.
Body of review
Overview of the market Elevated TG have traditionally been very difficult to treat adequately. Currently niacin, fibrates, or w3 fatty acids can be used to treat elevated TG and are often used concomitantly with statins and lifestyle modifications. Niacin safety and benefit have both been questioned based on relatively recent clinical trials. The AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) compared statin with statin plus extended-release niacin in 3414 subjects [17]. After 3 years, there was no benefit in the niacin group, but there was an increase in stroke in the niacin group, although not statistically significant. In the HPS2-THRIVE trial (Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events), statin was compared with statin plus niacin and laropiprant (an anti-flushing agent) in 25,673 subjects. Again, addition of niacin did not appear to have any outcome benefit but had increased incidence of serious adverse events (AE) but not an increase in stroke [18]. Additionally, niacin may be difficult to tolerate in the long term at the doses necessary to affect lipid lowering. Niacin is also contraindicated in liver disease and should be used cautiously in diabetes. The most commonly used fibrates are fenofibrate and gemfibrozil. Gemfibrozil has fallen out of favor in clinical use because of its effect on statin metabolism by inhibiting glucuronidation, resulting in increased risk of myopathy [19]. Fenofibrate showed no outcomes benefit when combined with statin in 5518 patients with type 2 diabetes mellitus in the ACCORD (The Action to Control Cardiovascular Risk in Diabetes) trial [20]. Fibrate use is also associated with increased gallstones and creatinine levels. It should be noted that post hoc analyses of several fibrate trials have shown cardiovascular benefit in a subgroup of patients with low HDL-C and high TG levels, but these findings are hypothesis-generating and not conclusive. w3 fatty acids are mainly composed of long-chain w3 fatty acids, including eicosapentaenoic acid (EPA) (C20:5n-3) and docosahexaenoic acid (DHA) (C22:6n-3) (Figure 1). These are obtained from fish oil and are not available from plant sources in any significant quantity. There are currently several prescription and multiple over-the-counter fish oil preparations. 2.1
Expert Opin. Pharmacother. (2015) 16(1)
w-3 carboxylic acids
Table 1. Triglyceride categories by ATP2 and ATP3. Triglyceride category
ATP II level (mg/dl)
ATP III level (mg/dl)
ATP II level (mmol/l)
ATP III level (mmol/l)
Normal Borderline-high High Very high
< 200 200 -- 399 400 -- 1000 > 1000
< 150 150 -- 199 200 -- 499 ‡ 500
< 2.26 2.26 -- 4.50 4.51 -- 11.29 > 11.29
< 1.69 1.69 -- 2.25 2.26 -- 5.63 ‡ 5.64
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ATP: Adult treatment panel.
O HO
EPA CA (FFA) O HO
DHA CA (FFA) O
H 5O EPA EE O C2H5O DHA EE
Figure 1. Structures of v3 EE and v3 CA (FFA). CA: Carboxylic acid; DHA: Docosahexaenoic acid; EE: Ethyl ester; EPA: Eicosapentaenoic acid; FFA: Free fatty acid.
The benefit of the prescription fish oils is a higher percent of OM3 per 1 g capsule and a usually greater degree of purification compared to over-the-counter preparations, resulting in less fishy taste and gastrointestinal (GI) symptoms. w3 compounds have a long safety history and are considered quite safe. Efficacy of w3 preparations is dependent on the dose utilized and the degree of hypertriglyceridemia. The maximum TG-lowering effect is seen with approximately 4 g of w3 preparations, and the greater the TG level, the greater the percent reduction of TG. w3 preparations in adequate doses generally decrease TG by 25 -- 30%. Three branded w3 capsules approved in the US are Lovaza (GlaxoSmithKline, Research Triangle Park, NC, USA), Vascepa (Amarin Pharma, Inc. Bedminster, NJ, USA) and
Omtryg (Trygg Pharmaceuticals, Oslo, Norway). Lovaza and Omtryg both contain w3 ethyl esters (w3 EE) of EPA and DHA. Vascepa is an w3 EE containing only EPA. A generic w3 EE equivalent to Lovaza has been introduced by Teva Pharmaceuticals (Petach Tikva, Israel) [21-24]. Epanova is FDA approved in the US but not yet marketed at the time of writing this article. A comparison of the lipid lowering effects of Epanova, Lovaza and Vascepa in severe hypertriglyceridemia without correction for placebo or control effect can be found in Table 2. Introduction to the compound w3 carboxylic acids (w3 CA) also called w3 free fatty acids (w3 FFA) (Box 1) are EPA and DHA in the FFA form versus 2.2
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Table 2. Comparison of Epanova with Lovaza and Vascepa.
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v3 dose
Epanova 2 g/d
Epanova 4 g/d
Lovaza 4 g/d
Vascepa 4 g/d
n = 100
n = 99
n = 42
n = 76
Parameter
BL
% Change
BL
% Change
BL
% Change
BL
% Change
TG Non-HDL-C TC VLDL-C HDL-C LDL-C ApoB
717 205 241 123 27 77 114
--25 --8 --6 --25 +7 +21 +6
655 225 254 126 29 90 118
--31 --8 --6 --35 +5 +26 +6
816 271 296 175 22 89 --
--44.9 --13.8 --9.7 --41.7 +9.1 +44.5 --
680 225 254 123 27 91 121
--27 --8 --7 --20 --4 --5 --4
% change values are not corrected for placebo or control results. Data modified from product information accessed online 1NOV2014. ApoB: Apolipoprotein B; BL: Baseline in mg/dl; g/d: g/day; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; N: Number; Non-HDL-C: Non-high-density lipoprotein cholesterol; TC: Total cholesterol; TG: Triglycerides; VLDL-C: Very-low-density lipoprotein cholesterol.
other available w3 preparations that can be considered prodrugs containing w3 EEs. w3 CA undergoes an additional step during the manufacturing process that hydrolyzes the w3 EE into w3 CA, which is readily absorbed in the GI tract. Transport across the intestinal wall is dependent on fat being in the FFA form. It is re-esterified within the intestinal cell for transport as a TG. In contrast, w3 EE, once consumed, needs to be hydrolyzed into the FFA form by carboxyl ester lipase, also called bile salt-dependent lipase. The carboxyl ester lipase is a pancreatic enzyme secreted when stimulated by ingestion of fat and is therefore meal dependent [25]. Chemistry Each gram of w3 CA contains at least 850 mg of polyunsaturated fatty acids, including multiple w3 fatty acids, with EPA and DHA being the most abundant [26]. Compared with the w3 EE Lovaza, w3 CA contains 75% EPA and DHA and w3 EE contains 84% EPA and DHA. Because the w3 EE has to undergo hydrolysis to be absorbed and w3 CA does not, approximately the same amount of EPA and DHA are available for absorption after hydrolysis of the w3 EE assuming complete hydrolysis of the w3 EE occurs [27]. 2.3
Pharmacodynamics Review of the literature concerning the TG-lowering mechanism of action of w3 compounds reveals gaps in our knowledge base. There is agreement that w3s decrease the hepatic synthesis of VLDL, increase b-oxidation of fatty acids, thus decreasing their availability for TG synthesis, and enhance the clearance of TG from VLDL and chylomicron particles by increasing LPL activity [28]. The result of these changes is a reduction in TG, VLDL and non-HDL-C, sometimes accompanied by an increase in LDL-C thought to be due to increased cholesterol content of LDL particles, not increased numbers of atherogenic apolipoprotein B (apoB) containing particles [29-31]. 2.4
126
Pharmacokinetics and metabolism After oral administration, w3 CA is directly absorbed in the small intestine, eventually entering the lymphatic system and the thoracic duct, and emptying into the superior vena cava. Maximum EPA plasma concentrations are achieved 5 -- 8 h after dosing with 4 g of w3 CA with low-fat meal conditions after repeat daily dosing for 2 weeks. Maximum DHA concentration is achieved under the same conditions in 5 -- 9 h. Steady-state concentrations of EPA and DHA are achieved within 2 weeks of repeat daily dosing. The EPA and DHA are distributed in phospholipids, TG and cholesterol esters. Metabolism of w3 CA is by oxidation in the liver similar to other fatty acids from the diet. Following repeat dosing, the half-life of EPA and DHA from w3 CA is 37 and 46 h, respectively. There is no renal excretion [26]. 2.5
3.
Clinical efficacy
Pharmacokinetic studies Originally, w3 CA underwent clinical trials as a treatment for Crohn’s disease but were not successful in preventing disease flares. The safety of the preparation was shown during those trials [32]. There have been four clinical trials with the w-3 CA, two focusing on TG lowering and two PK studies. These include two trials looking at pharmacokinetics and bioavailability of w-3 CA as both single dose and multiple dosing and two studies investigating clinical efficacy in two different fasting TG level populations. The ECLIPSE trial (Epanova compared to Lovaza in a pharmacokinetic single-dose evaluation trial) was a bioavailability four-way crossover study in 54 obese but otherwise healthy adults [27]. The purpose was to compare bioavailability of w3 CA to w3 EE during both low and high-fat meals. Each dosing period consisted of a 24-h collection of PK data analyzing EPA and DHA levels after a single 4-g dose of either w3 CA or w3 EE followed by either low- or high-fat meals for the entire day. The dose was taken either in the fasted state 3.1
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Total EPA+DHA plasma concentrations (nmol/ml)
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w-3 carboxylic acids
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Test: ω3 FFA, low-fat diet Reference: ω3 EE, low-fat diet
350 300 250 200 150 100 50 0 0
2
4
6
8
10
12
14
16
18
20
22
24
Time (h)
Figure 2. ECLIPSE low-fat diet -- total EPA + DHA plasma concentration. Mean (SD) total EPA + DHA concentration time profiles (baseline-adjusted change) after a single 4 g dose of w3 FFA (CA) vs w3 EE during the low-fat period. Reproduced with permission from [27]. DHA: Docosahexaenoic acid; EE: Ethyl ester; EPA: Eicosapentaenoic acid; FFA: Free fatty acid.
followed by low-fat meals throughout the 24 h PK period (low-fat period) or 30 min following a high-fat meal followed by high-fat meals throughout the 24 h PK period (high-fat period). A minimum of a 1-week washout occurred between dosing periods during which all subjects followed a Therapeutic Lifestyle Changes (TLC) diet. The AUC of the total EPA + DHA plasma concentrations versus time were fourfold higher for w3 CA vs w3 EE during the low-fat meal period (Figure 2) and 1.3-fold higher during the high-fat meal period. The conclusion was that w3 CA has increased bioavailability over w3 EE in the low-fat state, making it a viable option for use when patients follow a low-fat diet typically prescribed for hypertriglyceridemia. The ECLIPSE II trial was a 2-week multiple-dose PK study of 4 g of w3 CA versus w3 EE in 52 healthy subjects on lowfat diets, as high-risk cardiovascular patients are advised to follow a low-fat diet [33]. The w3 was dosed daily for 14 consecutive days, and levels of combined EPA and DHA were obtained. The baseline levels between the two groups after 7 days of the TLC diet were essentially equal. At 14 days, the w3 CA had a threefold greater EPA + DHA serum concentration than the w3 EE. Phase III studies The EVOLVE trial (The Epanova for lowering very high triglycerides) randomized 399 patients with TG between 500 and < 2000 mg/dl to either 4 g/day (g/d) of olive oil (OO) as control, 2 g/d of w3 CA and 2 g/d of OO, 3 g/d of w3 CA and 1 g/d of OO or 4 g/d of w3 CA. The study was 3.2
12 weeks in length and a double-blind, international, randomized, parallel group design [29]. The baseline demographics of the four treatment groups were similar. TG were lowered 4.3, 25.9, 25.5 and 30.9% by control (4 g/d OO), 2 g/d w3 CA (+2 g/d OO), 3 g/d w3 CA (+1 g/d OO) and 4 g/d w3 CA, respectively (all values % least squares geometric mean). All of the lipoprotein and biomarker results can be seen in Table 3. As has been seen with other lipid-lowering agents, the higher the baseline TG value, the greater the reduction in TG level. In addition to TG being lowered, other apparent favorable changes occurred in non-HDL-C, VLDL-C, remnant-like particle cholesterol (RLP-C) and apoCIII. The LDL-C, corrected for control changes, increased by 19% in the 2 and 4 g/d w3 CA arms, but apoB only increased 3.8%, which was not statistically different than the placebo arm. This suggests that the increase in LDL-C is due to increased cholesterol content of the LDL particles, not an increase in particle number, and thus is not likely to mean increased atherogenic potential. Treatment-emergent AEs (TEAEs) occurring in > 3% of patients are shown in Table 4. The TEAEs that appear related to w3 CA are overall GI complaints and more specifically diarrhea and nausea as well as eructation. The ESPRIT trial (A highly bioavailable w3 FFA formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia) was a double-blind, parallel-group study in 647 patients on statin therapy with fasting TG levels of ‡ 200 and < 500 mg/dl [34]. Patients were at high risk for CVD and on maximally tolerated statin or statin with ezetimibe prior to randomization.
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Table 3. EVOLVE trial partial lipid results (modified intent-to-treat population).
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Variable
TG, mg/dl Baseline EOT % D LSGM (95% CI) Non-HDL-C, mg/dl Baseline EOT % D LSGM (95% CI) HDL-C, mg/dl Baseline EOT % D LSGM (95% CI) Total C, mg/dl Baseline EOT % D LSGM (95% CI) LDL-C, mg/dl Baseline EOT % D LSGM (95% CI) VLDL-C, mg/dl Baseline EOT % D LSGM (95% CI) RLP-C, mg/dl Baseline EOT % D LSGM (95% CI) Apo B, mg/dl Baseline EOT % D LSGM (95% CI) Apo CIII, mg/dl Baseline EOT % D LSGM (95% CI)
Control, OO 4g/d n = 98
v3 CA 2 g/d n = 99
v3 CA 3 g/d n = 97
v3 CA 4 g/d n = 99
682 642 -4.3 (-13.1 to 5.4)
717 554 -25.9z (-32.8 to -18.1)
728 544 -25.5z (-32.4 to -17.8)
655 513 -30.9§ (-37.3 to -23.7)
215 217 2.5 (-2.3 to 7.6)
205 209 -7.6* (-12.0 to -3.0)
215 197 -6.9* (-11.4 to -2.2)
225 211 -9.6z (-14.0 to -5.1)
28.7 30.0 1.9 (-2.0 to 6.0)
27.3 29.0 7.4 (3.2 to 11.7)
28.0 28.5 3.8 (-0.3 to 8.0)
28.7 29.0 5.8 (1.7 to 10.1)
246 244 3.2 (-1.0 to 7.5)
241 233 -5.4* (-9.3 to -1.4)
244 228 -4.9 (-8.7 to -0.8)
254 247 -7.5z (-11.2 to -3.5)
78.2 86.3 3.0 (-2.9 to 9.3)
77.3 93.3 19.2z (12.3 to 26.5)
81.0 95.0 14.3 (7.6 to 21.4)
90.3 110 19.4§ (12.4 to 26.8)
125 113 -8.5 (-16.6 to 0.3)
123 98.0 -26.6z (-33.1 to -19.4)
124 92.8 -26.4z (-33.0 to -19.2)
126 87.0 -33.0§ (-39.0 to -26.4)
52.3 41.0 3.4 (-10.1 to 18.9)
44.5 37.0 -20.7* (-30.9 to -8.9)
42.5 34.5 -22.6* (-33.1 to -10.6)
43.0 33.0 -27.5§ (-36.9 to -16.7)
110 116 0.9 (-3.6 to 5.5)
114 120 3.8 (-0.7 to 8.5)
112 115 2.3 (-2.4 to 7.2)
118 122 3.8 (-0.8 to 8.5)
24.0 26.0 1.6 (-5.0 to 8.6)
24.5 21.0 -10.9* (-16.6 to -4.8)
26.0 21.0 -12.2z (-18.0 to -5.9)
24.5 21.0 -14.4§ (-19.9 to -8.5)
Adopted from [29]. *Significantly different from the OO group, p < 0.05. z Significantly different from the OO group, p < 0.01. § Significantly different from the OO group, p < 0.001. % D LSGM: Percent change by least square geometric mean; Apo B: Apolipoprotein B; apo CIII: Apolipoprotein CIII; C: Cholesterol; CA: Carboxylic acid; EOT: End of treatment; g/d: g/day; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; n: Number; OO: Olive oil; RLP: Remnant-like particle; TG: Triglycerides; VLDL: Very-low-density lipoprotein.
They were randomized to placebo 4 g/d (OO), 2 g/d w3 CA (+2 g/d OO) or 4 g/d of w3 CA and treated for 6 weeks. The primary objective was to evaluate the efficacy of adding 2 or 4 g/d of w3 CA to hypertriglyceridemic patients on statin 128
to see the effect on non-HDL-C and TG after a 6-week diet and statin stabilization period. TG were reduced by 5.9, 14.6 and 20.6% for OO, w3 CA 2 g/d and w3 CA 4 g/d, respectively. Compared with OO, changes in TG by both doses of
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Table 4. EVOLVE Study TEAEs occurring in > 3% of subjects in safety population.
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System
Gastrointestinal All Upper abd pain Diarrhea Eructation Nausea Vomiting Infections All Nasopharyngitis Metabolism and Nutrition disorders Musculoskeletal disorders Nervous system disorders Skin disorders
Control OO 4 g/d n = 99
v3 CA 2 g/d n = 100
v3 CA 3 g/d n = 101
v3 CA 4 g/d n = 99
7 1 2 1 1 1
(7.1) (1.0) (2.0) (1.0) (1.0) (1.0)
19 (19.0) 4 (4.0) 10 (10.0) 3 (3.0) 6 (6.0) 2 (2.0)
21 (20.8) 1 (1.0) 6 (5.9) 4 (4.0) 9 (8.9) 4 (4.0)
27 (27.3) 1 (1.0) 10 (10.1) 4 (4.0) 5 (5.1) 0 (0.0)
11 (11.1) 2 (2.0)
14 (14.0) 7 (7.0)
7 (6.9) 3 (3.0)
12 (12.1) 1 (1.0)
2 (2.0)
0 (0.0)
1 (1.0)
4 (4.0)
6 (6.1) 0 (0.0) 0 (0.0)
5 (5.0) 6 (6.0) 4 (4.0)
6 (5.9) 5 (5.0) 1 (1.0)
3 (3.0) 4 (4.0) 2 (2.0)
Values are given as number (percent). Adopted from [29] with permission. Abd: Abdominal; CA: Carboxylic acid; g/d: g/day; OO: Olive oil; n: Number; TEAE: Treatment emergent adverse event.
w3 CA were statistically significant (p < 0.001). Non-HDL-C was reduced by 0.9, 3.9 and 6.9% for OO, w3 CA 2 g/d and w3 CA 4 g/d, respectively. Compared with OO, 2 g/d w3 CA significantly reduced non-HDL-C (p < 0.05), as did the 4 g/d dose (p < 0.0001). See Table 5 for additional results. Safety data related to TEAEs occurring in > 3% of patients are shown in Table 6. Similar to the EVOLVE trial, the only TEAEs that appear related to w3 CA are overall GI complaints and more specifically diarrhea and nausea, all of which were reported as transient and mild.
Post-marketing surveillance (cardiovascular outcomes trials)
3.3
A large Phase III outcomes trial is planned for w3 CA. The study is entitled ‘A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction with EpaNova in HiGh Cardiovascular Risk PatienTs with Hypertriglyceridemia’ (STRENGTH) [35]. Thirteen thousand high CVD risk patients on statin (+/- ezetimibe) therapy with TG ‡ 200 and < 500 mg/ dl and HDL < 40 mg/dl in men or HDL < 45 mg/dl in women will be randomized 1:1 to w3 CA 4 g/d versus control (corn oil) 4 g/d. The study will continue for ~ 3 -- 5 years until 1600 primary events are accrued. Results are expected in 2019. An additional outcomes trial for w3 EE containing EPA only (Vascepa) is currently under way and expected to have results by the end of 2016. The study is called REDUCE-IT and is ‘A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients with Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/d AMR101 for Preventing the Occurrence of a First Major
Cardiovascular Event.’ It will enroll 8000 high-risk patients and tests 4 g/d of EPA w3 EE against placebo (mineral oil) [36]. 4.
Safety and tolerability
w3 compounds have a long history of use and are generally considered safe. In 1997, the FDA concluded that total intakes (from diet and supplements) of EPA and DHA up to 3 g/d were generally recognized as safe (GRAS) and approved a prescription w3 medication at 4 g/d in 2004. The potential major AEs associated with w3 use are increased bleeding, impaired immune function and impaired glucose metabolism. In 2012, the European Food Safety authority (EFSA) reviewed the available w3 information and concluded that DHA plus EPA usage up to 5 g/d (or EPA alone up to 1.8 g/d) did not have any safety concerns for adults [37]. The minor AEs associated with w3 are GI symptoms of eructation, nausea and diarrhea or loose stools. Safety data from the w3 CA trials appear favorable with low rates of moderate or severe AEs. A summary of the safety data from the two Phase III TG lowering w3 CA studies is below. EVOLVE treatment emergent AEs (TEAEs) occurring in > 3% of patients are shown in Table 4. The only TEAEs that appear related to w3 CA are overall GI complaints and more specifically diarrhea and nausea as well as perhaps eructation. The majority of AEs were considered mild. ESPRIT safety data related to TEAEs occurring in > 3% of patients are shown in Table 6. Similar to the EVOLVE trial, the only TEAEs that appear related to w3 CA are overall GI complaints and more specifically diarrhea and nausea, all of which were reported as transient and mild.
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Table 5. ESPIRIT study results.
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Variable TG, mg/dl Baseline EOT % D LSGM (95% CI) Non-HDL-C, mg/dl Baseline EOT % D LSGM (95% CI) HDL-C, mg/dl Baseline EOT % D LSGM (95% CI) Total C, mg/dl Baseline EOT % = LSGM (95% CI) LDL-C, mg/dl Baseline EOT % D LSGM (95% CI) VLDL-C, mg/dl Baseline EOT % D LSGM (95% CI) RLP-C, mg/dl Baseline EOT % D LSGM (95% CI) Apo B, mg/dl Baseline EOT % D LSGM (95% CI) Apo CIII, mg/dl Baseline EOT % D LSGM (95% CI)
Statin + control OO 4g/d n = 211
Statin + v3 CA 2 g/d n = 209
Statin + v3 CA 4 g/d n = 207
280 268 -5.9 na
284 244 -14.6§ na
287 233 -20.6§ na
135 136 -0.9 na
140 136 -3.9* na
139 132 -6.9§ na
38.8 39.8 2.2 na
38.7 39.8 2.6 na
38.8 40.3 3.3 na
174 176 0.5 (-1.2 to 2.2)
179 176 -1.71 (-3.4 to -0.0)
178 172 -3.83§ (-5.4 to -2.1)
91.7 92.8 1.1 (-1.6 to 3.8)
92.3 96.6 4.6* (1.8 to 7.4)
93.6 94.2 1.3 (-1.4 to 4.1)
45.7 43.6 -5.9 (-10.4 to -1.1)
46.9 39.8 -14.3z (-18.4 to -10.0)
47.2 37.5 -21.5§ (-25.2 to -17.5)
52.3 41.0 3.4 (-10.1 to 18.9)
44.5 37.0 -20.7 (-30.9 to -8.9)
42.5 34.5 -22.6 (-33.1 to -10.6)
93.8 94.4 0.3 (-1.6 to 2.2)
94.5 95.6 0.7 (-1.2 to 2.6)
95.9 93.8 -2.1* (-4.0 to -0.3)
24.0 26.0 1.6 (-5.0 to 8.6)
24.5 21.0 -10.9 (-16.6 to -4.8)
26.0 21.0 -12.2 (-18.0 to -5.9)
Adopted from [34] with permission. *Significantly different from the OO group, p < 0.05. z Significantly different from the OO group, p < 0.01. § Significantly different from the OO group, p < 0.001. % D LSGM: Percent change by least square geometric mean; Apo B: Apolipoprotein B, apo CIII: Apolipoprotein CIII; C: Cholesterol; CA: Carboxylic acid; EOT: End of treatment; g/d: g/day; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; n: Number; Na: Not available; OO: Olive oil; RLP: Remnant-like particle; TG:Triglycerides; VLDL: Very-low-density lipoprotein.
5.
Regulatory affairs
w3 CA (Epanova) was approved by the US FDA in May 2014 for use in patients with TG ‡ 500 mg/dl as an adjunct 130
to diet therapy. As of November 2014, Epanova was not yet available on the market for prescribing. Omthera Pharmaceuticals (Princeton, NJ, USA) is now owned by AstraZeneca (London, UK).
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Table 6. ESPRIT Study TEAEs occurring in > 3% of subjects in safety population. Values are given as number (percent).
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System
Gastrointestinal All Diarrhea Nausea Infections All Musculoskeletal disorders Nervous system disorders
Statin + control OO 4 g/d n = 215
Statin + v3 CA 2 g/d n = 215
Statin + v3 CA 4 g/d n = 216
19 (8.8) 5 (2.3) 3 (1.4)
29 (13.5) 13 (6.0) 6 (2.8)
58 (26.9) 36 (16.7) 13 (6.8)
21 (9.8) 11 (5.1) 3 (1.4)
7 (3.3) 7 (3.3) 2 (0.9)
17 (7.9) 10 (4.6) 8 (3.7)
Adopted from [34] with permission. CA: Carboxylic acid; g/d: g/day; n: Number; OO: Olive oil; TEAE: Treatment emergent adverse event.
6.
Conclusion
w3 CA appears safe and effective for lowering TG. There are potential advantages to the CA (FFA) form due to increased absorption from the GI tract without dependence on pancreatic enzymes, which are triggered by meals, especially high-fat meals. In addition to TG lowering, non-HDL-C, total cholesterol and apoCIII are also decreased. LDL-C is increased, but apoB is not significantly increased, suggesting an increase in cholesterol content of LDL particles, without a significant increase in atherogenic particle numbers. This can change the more atherogenic small, dense LDL particles into less atherogenic larger LDL particles as well as decrease the number of TG- rich remnants that are in the circulation. All of these changes should lead to a decrease in atherosclerosis, which could potentially result in decreased CV events. 7.
Expert opinion
w3 CA is a newly available source of prescription w3 fish oil that is significantly less dependent on concomitant food intake than other currently available w3 products. The other w3 products are w3 EEs that require pancreatic enzymes for breakdown in the gut before absorption by the small bowel. w3 EEs are best absorbed with a high-fat meal, which is contraindicated in patients with hypertriglyceridemia. w3 CA is readily absorbed in the small intestine without the need for pancreatic enzymatic action and w3 CA has 3 -- 4 times the bioavailability compared to w3 EE in low-fat meal situations. The lower 2 g/d dose of w3 CA has been shown to reduce triglycerides by 25%, which was a significant reduction. This lower dose may offer better patient compliance and adherence to therapy because of less capsules per day, less need to take with meals and perhaps fewer AEs then the 4 g dose. These same factors may be an inducement for physicians to prescribe the w3 CA over the w3 EE preparations. w3 CA at 2 and 4 g/d appears to have similar lipid effects as the EPA EE preparation on TG and non-HDL-C but an increase in LDL-C
(with minimal increase in apoB) versus a slight decline in LDL-C and apoB for EPA EE. With potent statins and newer classes of LDL-C lowering drugs, this may not be a significant difference factor. The combination EPA and DHA EE preparation shows a better effect on decreasing TG and non-HDL-C then w3 CA but a 44% increase in LDL-C, which may be significant. The major question that needs answering is whether w3 preparations used with statin therapy will be beneficial to the patient and decrease the incidence of CVD. The clinical trial post hoc data, genomic data and population studies suggest that if the LDL-C is controlled and TG are increased (> 200 mg/dl for now), there should be additional cardiovascular benefit to lowering TG. The two large well-designed outcomes trials previously described should help answer this question in the next several years. I believe that lowering elevated TG (perhaps > 150 mg/dl or even lower) will have CV benefit and will be shown with a clinical trial that is properly designed and carried out. Combination therapy with w3 CA and a statin may be the combination of choice in the future if clinical trial results show benefit to lowering TG. The attractiveness of a combination statin/w3 compound is the lack of interaction between the two and the low AE profile of the w3 in comparison to previous combinations of statin and fibrate or niacin. Also, patients are more accepting of an w3 preparation because they consider it a natural substance and this may contribute to initial acceptance and long-term adherence. There is still a significant residual risk of CVD despite adequate LDL-C lowering with statins, hopefully the addition of w3 medications to lower TG will have a significant effect on reducing that residual risk. We anxiously await the results of the two w3 outcomes trials.
Acknowledgement The author thanks Kevin C Maki, PhD for kindly reviewing the manuscript and making editorial suggestions.
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Declaration of interest EM Roth has received speakers bureau for AstraZeneca. The author has no other relevant affiliations or financial Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
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Affiliation Eli M Roth MD FACC FNLA Professor, Cardiology University of Cincinnati, Sterling Research Group, 375 Glensprings Dr. 2nd Floor, Cincinnati, OH 45246 USA Tel: +1 513 671 8080; Fax: +1 513 671 8090 E-mail: [email protected]
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