The recent National Lipid Association and the International Atherosclerosis Society recommendations advocate that non-HDL cholesterol (HDL-C) rather than LDL cholesterol (LDL-C) becomes the primary target of therapy [1▪,2▪]. This is based on the premise that the triglyceride-rich lipoprotein cholesterol (TRL-C) fraction of non-HDL-C (i.e., non-HDL-C minus LDL-C) is also atherogenic, at least as comparable to LDL-C, and therefore represents a more valid surrogate to target for cardiovascular risk reduction . Analyses from the statin outcome trials have demonstrated that when non-HDL-C and LDL-C are discordant, risk for recurrent major adverse events follows non-HDL-C. In patients in the statin trials with LDL-C less than 100 mg/dL but with a non-HDL-C greater than 130 mg/dL, the hazard ratio was 1.32 compared with 1.21 for patients with LDL-C less than 100 mg/dL and non-HDL-C less than 130 mg/dL . The Copenhagen Heart Study clearly demonstrated that as triglyceride levels rise, non-HDL-C also increases due to the increase in TRL-C (remnant cholesterol) while LDL-C and HDL-C both decrease; however, the risk for cardiovascular events increase, thereby implicating TRL-C as causal for cardiovascular disease (CVD) . The causality of TRL-C for atherosclerosis has also been supported by numerous genome-wide association studies that link greater than expected cardiovascular risk to polymorphisms associated with triglyceride elevation due to lifelong exposure . Meanwhile the causal role of low HDL-C based on gene-wide association studies remains ambiguous . Based on these recent findings, the conventional belief that hypertriglyceridemia is associated with increased cardiovascular risk due to low HDL-C has been challenged and the causal factor is indeed the TRL-C. To further support this hypothesis, there is evidence that the triglyceride-rich lipoproteins are readily taken up by the macrophages and a large percent of the cholesterol in the arterial plaque are derived from these lipoproteins .
In the presence of increased hepatic lipogenesis, the liver secretes enlarged, more triglyceride-rich VLDL, which due to the larger surface area attracts apolipoprotein CIII (apoCIII). Once secreted, the apoCIII-rich VLDL is more slowly catabolized by lipoprotein lipase resulting in increased VLDL-C and remnant cholesterol (TRL-C), thereby increasing non-HDL-C. This slower conversion of the VLDL to LDL is also associated with retention of apoCIII on LDL and the formation of small dense LDL . Both small dense LDL-C and LDL enriched with apoCIII (which likely have significant overlap) are associated with much higher cardiovascular risk compared with large buoyant LDL or LDL without apoCIII. In fact, there is considerable evidence that only small dense LDL-C and not large LDL-C is associated with cardiovascular risk [10▪▪]. Similar findings have been demonstrated for LDL with apoCIII compared with LDL without apoCIII .
Omega-3 fatty acids (OM3-FAs) containing predominantly eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) down-regulate hepatic lipogenesis, reducing the size of the secreted VLDL and thereby reduce apoCIII enrichment . This results in a significant lowering of VLDL-C and remnant cholesterol (TRL-C) as well as a shift of small dense LDL to large buoyant LDL with less apoCIII  (Fig. 1). These cholesterol compositional changes are associated with only a modest decline in apolipoprotein B (apoB) levels. This review focuses on the potential role by which a complex mixture of omega-3s may beneficially modify cardiovascular risk by modifying the cholesterol composition of atherogenic lipoproteins. This hypothesis is being tested in the STRENGTH trial, which is enrolling 13 000 patients on statins at high cardiovascular risk with hypertriglyceridemia paired with low HDL-C treated with a OM3-carboxylic acids (OM3-CA) compared to corn oil (http://clinicaltrials.gov/show/NCT02104817). In light of the growing prevalence of metabolic syndrome throughout the world and the associated elevation of non-HDL-C, there is renewed interest in the role of OM3-FAs as a therapy for dyslipidemia, to combine with statins to address the well known residual risk in this population.
CLINICAL DIFFERENCES IN PRESCRIPTION OMEGA-3 FATTY ACID FORMULATIONS
There are three regulatory approved OM3-FAs for the treatment of hypertriglyceridemia. Two formulations are complex mixtures of OM3-FAs containing primarily EPA and DHA either as ethyl esters [omega-3 ethyl esters (OM3-EE), Lovaza in the USA, or Omacor outside the USA, Lotriga in Japan] or as free FAs (OM3-CA, Epanova). The third product is a pure EPA ethyl ester (icosapentyl ethyl, Vascepa). OM3-EE are dosed as two 1 g capsules twice a day with meals (Lovaza can be prescribed as four 1 g capsules once a day with a meal). OM3-CA due to improved bioavailability is dosed as two 1 g or four 1 g capsules once a day without regards to meals. OM3-EE are poorly absorbed unless taken with a high fat meal because prior to intestinal absorption the ethyl ester bond must be hydrolyzed into the free FA from pancreatic lipases, which are secreted in response to fat in the diet . Therefore, OM3-EE are prodrugs that require intestinal digestion while OM3-CA is already hydrolyzed into the absorbable form and formulated with a novel gelatin capsule to prevent the upper gastrointestinal upset associated with free FAs and to maintain stability. OM3-CA (Epanova) has an approximately four-fold to six-fold increase in EPA and DHA bioavailability under low fat dietary conditions, a potentially important clinical finding for patients adhering to a low-fat diet as part of their treatment plan . With chronic dosing, head-to-head comparisons have shown that OM3-CA has at least two-fold greater bioavailability to the ethyl ester formulations and this translates into improved triglyceride lowering efficacy at a lower dose .
Improved bioavailability with OM3-CA causes greater efficacy, with a lower 2 g dose and doubling the dose resulting in enhanced triglyceride and non-HDL-C reduction. However, the additional lipid-lowering efficacy comparable to statins appears to be curvilinear (triglyceride lowering of 25% at 2 g and 31% at 4 g in patients with severe hypertriglyceridemia) [17▪▪]. The cardiovascular benefits of OM3-FAs are linked to higher levels of EPA, DHA, and docosapentanoic acid (DPA) that are independent of triglyceride lowering . OM3-FAs may have antithrombotic, anti-inflammatory, and antiarrhythmic effects that potentially are responsible for a correlation of higher plasma levels of EPA, DHA, and DPA with reduced total and cardiovascular mortality . Low dose supplementation OM3-FA outcome trials such as GISSI  and JELIS  have demonstrated a reduction in major adverse events in populations with higher baseline levels of EPA and DHA (Italy and Japan, respectively), but other trials such as ORIGIN , which involved a population (predominately North America) with much lower baseline levels of EPA and DHA, failed to demonstrate a clinical benefit with the same low therapeutic dose (1 g of OM3-EE, Omacor). In the JELIS trial, the baseline EPA level was 83 μg/ml and increased to 172 μg/ml with 2 g of pure EPA [icosapentyl ester (IPE)]. The cardiovascular benefits with IPE in the JELIS trial correlated with the on-treatment EPA levels . Based on these findings that only much higher achieved levels of OM3-FAs will result in lower cardiovascular mortality, it is important to utilize omega-3 therapies that can indeed increase the plasma levels associated with a clinical benefit. In the ECLIPSE II trial conducted in the USA, the baseline EPA was 9.5–13 μg/ml and after 2 weeks of chronic dosing in patients treated with OM3-EE (Lovaza) the EPA level increased to 34 μg/ml, approximately a third of the EPA levels of the Japanese population at baseline in the JELIS trial. In comparison, OM3-CA increased the EPA level to 143 μg/ml, which is approximately equivalent to the levels of EPA associated with cardiovascular benefits in the JELIS trial  (Fig. 2). The Cardiovascular Health Study and a recent meta-analysis have also linked higher EPA, DHA, and DPA with lower cardiovascular mortality . The plasma levels of EPA, DHA, and DPA that are associated with lower cardiovascular mortality were achieved in the clinical trials utilizing high doses of OM3-CA; dietary supplements of OM3-FAs or even lower prescription doses of OM3-EE may not be sufficient to bring the plasma levels of OM3-FAs to a threshold in which cardiovascular benefits can be derived.
In addition to beneficial lipoprotein changes, OM3-FAs may have anti-inflammatory and antithrombotic effects that are particularly welcomed in statin-treated patients. Statin therapy is known to increase desaturase activity, which will enhance conversion of short chain polyunsaturated fats (PUFA) to long chain PUFA (LC-PUFA) . Therefore statin therapy increases the production of arachidonic acid, a LC-PUFA. A theoretical benefit of EPA is to competitively inhibit arachidonic acid resulting in an anti-inflammatory and antithrombotic effect. In a clinical trial in hypercholesterolemic patients, simvastatin increased the arachidonic acid:EPA ratio from 15.5 to 18.8 (P < 0.01) due to stimulation of desaturase activity. Furthermore, there are known polymorphisms of the fatty acid desaturase (FADS) genes that affect LC-PUFA levels. African-American have a high prevalence (approximately 80%) of FADS polymorphisms that results in enhanced desaturase activity and leads to a higher arachidonic acid:EPA ratio . Hispanics, on the other hand, have a high prevalence (about 67%) of FADS polymorphisms associated with lower desaturase activity and also have a higher arachidonic acid: EPA ratio, which is due to lower EPA levels rather than higher arachidonic acid levels . The potential clinical consequence of widespread statin use resulting in a higher arachidonic acid:EPA ratio means that much higher doses of OM3-FAs may be necessary to achieve a therapeutic benefit, especially in high cardiovascular risk populations and the high prevalence of FADS polymorphisms population in the USA. This issue calls into question the value of some ongoing outcome trials utilizing a low dose of OM3-FA (1 g) to evaluate a clinical benefit in the North American population [The VITamin D and OmegA-3 TriaL (VITAL) is an ongoing randomized clinical trial in 25 874 US men and women investigating whether taking daily dietary supplements of vitamin D3 (2000 IU) or OM3-FAs (Omacor fish oil, 1 g) reduces the risk of developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses (https://clinicaltrials.gov/show/NCT01169259)].
COMPARISON OF PRESCRIPTION OMEGA-3 CLINICAL TRIALS FOR DYSLIPIDEMIA
There have been three relatively recent trials (MARINE, EVOLVE, and OMTRYG) to evaluate the effects of the different prescription omega-3 therapies in patients with severe hypertriglyceridemia [28,17▪▪,29]. Although these were not head-to-head comparison trials, the sample sizes were comparable, with similar inclusion criteria and utilization of the same central laboratory (Medpace Labs). These three trials demonstrated that prescription of OM3-FAs significantly lowered triglycerides by approximately 25% and non-HDL-C by 9% from baseline to end of treatment (Table 1). The three trials utilized different controls (mineral oil, olive oil, and vegetable oil) that resulted in a varied response for placebo corrected differences. For the two OM3-FAs containing a complex mixture of predominately EPA and DHA, there was a shift of VLDL-C to LDL-C and therefore a decrease in apoCIII rich LDL and an increase in HDL-C. The major difference between the two products containing EPA and DHA was the equivalent triglyceride and non-HDL-C lowering with 2 g of OM3-CA (Epanova) compared to 4 g of OM3-EE (Lovaza and Omtryg), due to enhanced bioavailability of OM3-CA. With IPE 2 g twice a day with meals (Vascepa) as a pure EPA product, there was a similar decrease in triglycerides and non-HDL-C without an increase in LDL-C and HDL-C. Therefore DHA appears to have a more prominent role in shifting VLDL-C to LDL-C and raising HDL-C, which also has been documented in head-to-head EPA vs. DHA clinical trials .
In patients with mixed dyslipidemia (triglycerides between 200 and 500 mg/dL), there have also been three clinical trials that have documented similar differences with regards to changes in LDL particle size and small dense LDL compared with OM3-FAs containing EPA and DHA vs. EPA [31▪▪,32–36]. In the COMBOS and ESPRIT trials, OM3-EE (Lovaza) and OM3-CA (Epanova), respectively, significantly lowered non-HDL-C, increased LDL particle size, and decreased small LDL particles. In the COMBOS trial, EPA and DHA ethyl esters in combination with simvastatin 20 mg/day compared with placebo along with simvastatin decreased VLDL particle size and concentration and increased LDL particle size (all P < 0.05) without altering LDL particle concentration . Similarly, when the dosage of simvastatin was 40 mg/day, compared with placebo, EPA and DHA ethyl esters reduced mean VLDL particle size and increased LDL particle size . The total VLDL and LDL particle concentrations were not altered by EPA and DHA ethyl esters, relative to placebo, but large VLDL and intermediate-density lipoprotein particle concentrations were lowered and large LDL particle concentration was increased . See Table 2 for other results from the COMBOS, ANCHOR, and ESPRIT trials. A study in mixed dyslipidemia of lipoprotein particle size and concentration changes with atorvastatin in combination with EPA and DHA ethyl esters vs. atorvastatin with placebo also demonstrated a mean increase in LDL particle size accompanied by a reduction in small LDL particle concentration and an increase in large LDL particle concentration .
The ESPRIT study also demonstrated similar findings with a significant increase in large LDL particles with 4 g of OM3-CA containing both EPA and DHA with a subsequent analysis also showing a shift in small dense LDL-C to large LDL-C  (Fig. 3). In light of the ARIC trial demonstrating that only small LDL-C but not large LDL-C is associated with cardiovascular risk [10▪▪], this analysis highlights the importance of distinguishing the type of LDL-C increase (i.e., small vs. large LDL-C) for a specific therapy that also lowers total non-HDL-C in combination with statins. The increase in LDL particle size was dependent on a drop in triglycerides below a certain threshold. This triglyceride threshold is specific to each individual, but is usually within the range of 100–250 mg/dL . Along with significant non-HDL-C and triglyceride reduction, all three OM3-FAs, whether EPA and DHA or EPA alone, also reduced lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and remnant-lipoprotein cholesterol (RLP-C) consistently [31▪▪,32–36]. These two biomarkers are linked to markedly increased risk for CVD [39,40].
DIFFERENCES BETWEEN OMEGA-3 FATTY ACIDS AND FIBRATES
Both fibrates and OM3-FAs lower triglycerides and non-HDL-C, and there appears to be modest additive effects when combined for the treatment of severe hypertriglyceridemia, suggesting that they have different mechanisms of action. There is also a documented difference between these two classes of triglyceride lowering therapies that may affect the ability of these treatments to reduce cardiovascular events. An important issue that has not been recognized until recently is the prominent effect fenofibrate has on raising PCSK9 levels. Based on recent pharmacokinetic studies with the anti-PCSK9 monoclonal antibodies (mAbs), fenofibrate increases PCSK9 levels by more than 50% and by almost as much as statin therapy, while OM3-FAs have either a neutral or slightly lowering effect on PCSK9 levels [41,42]. This increase in PCSK9 levels may explain the previously reported decreased non-HDL-C lowering effect due to a greater LDL-C raising effect when fenofibrate is combined with high dose statins compared to low dose statins or monotherapy. In patients with hypertriglyceridemia, fenofibrate monotherapy lowered non-HDL-C by 16% but when combined with statins the incremental non-HDL-C was only 4% . Clinical trials with fenofibrate have consistently shown a negative dose response for non-HDL-C when combined with higher doses of statins. The opposite appears to be true with OM3-FAs. In the ESPRIT trial, OM3-CA had a greater non-HDL-C lowering effect in patients on high vs. low dose statin . A potential explanation for the adverse outcome for women in the ACCORD trial without hypertriglyceridemia or in the FIRST trial  [a Carotid Intima Medial Thickness (CIMT) progression trial adding fenofibric acid to statins in the subset of patients who were statin naïve] is the adverse effect of fibrates on increasing PCSK9 levels and thereby offsetting some of the LDL-lowering benefits of statins. This issue is especially relevant in light of guidelines that strongly advocate for maximizing the statin at high doses to best manage cardiovascular risk.
POTENTIAL MECHANISM FOR REDUCING RESIDUAL RISK
OM3-FAs containing both EPA and DHA or EPA alone in combination with statins lowers triglycerides and non-HDL-C. The non-HDL-C reduction in patients with mixed dyslipidemia (triglycerides between 200 and 500 mg/dL) is due to a decrease in VLDL-C and remnant cholesterol (TRL-C) with a modest decrease, neutral effect, or slight increase in LDL-C (depending on baseline LDL-C levels). OM3-FAs containing DHA also shift small dense LDL-C to large LDL-C and modestly improves HDL-C. The potential cardiovascular benefits of these compositional cholesterol changes are being tested in two large outcome trials. REDUCE-IT (Reduction of Cardiovascular Events With EPA – Intervention Trial) is evaluating the effects of 4 g of icosapentyl ethyl compared with mineral oil as the placebo in 8000 patients with either established CVD or at high risk for CVD with hypertriglyceridemia (>150 mg/dL initially and later increased to 200 mg/dL) on statin therapy (https://clinicaltrials.gov/show/NCT01492361). The trial recently completed enrollment and will likely complete in the next 2–3 years. The STRENGTH trial is specifically targeting the high-risk population with both elevated triglycerides and low HDL-C with 4 g of OM3-CA vs. corn oil as a control (http://clinicaltrials.gov/show/NCT02104817). In previous cardiovascular outcome trials with fenofibrate (ACCORD Lipid)  and niacin (AIM-HIGH) , this population with both elevated triglycerides paired with low HDL-C at high residual risk despite statin therapy saw a benefit with triglyceride-lowering therapy. The ACCORD trial is especially relevant, finding that fenofibrate reduced major adverse cardiac events by 31% in the prespecified subgroup in the upper tertile of triglycerides (>203 mg/dL) and the lower teritile of HDL-C (HDL-C < 32 mg/dL), but the P-value for an interaction was 0.06 (not significant) . In this subgroup, TRL-C was reduced by 9 mg/dL while the LDL-C was increased by 9 mg/dL resulting in a negligible overall change in non-HDL-C. This subgroup analysis provides hypothesis-generating support for therapies that shift TRL-C (or VLDL-C) to LDL-C and also convert small LDL-C to large LDL-C. Other cardiovascular outcome trials such as PROACTIVE with pioglitazone  and EMPA-REG with empagliflozin, in which there was also triglyceride reduction with a shift from small LDL-C to large LDL-C, showed that there appeared to be a cardiovascular benefit from such changes . It is important to note that other improvements in cardiovascular risk factors such as blood pressure reduction due to a reduction in blood volume were also greater in the empagliflozin group in EMPA-REG. Regardless, the STRENGTH trial is addressing one of the most important clinical questions regarding the management of dyslipidemia; whether non-HDL-C reduction by lowering TRL-C without adversely raising total cholesterol, including shifting small to large LDL-C will result in a cardiovascular benefit. This 13 000 patient trial is well underway and will hopefully answer this question in the coming years.
The available data from observational investigations, including studies of genetic variants that alter levels of triglycerides and TRL-C provide strong and consistent evidence to support a causal relationship between elevations in triglycerides and TRL-C and greater risk for atherosclerotic cardiovascular disease (ASCVD). Evidence from RCTs of interventions to treat such elevations is limited by the fact that no large-scale trial has been completed in which patients were selected on the basis of triglyceride elevation and treated with an agent that substantially lowers triglycerides and TRL-C. Three such trials are underway: REDUCE-IT, STRENGTH, and PROMINENT (The Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN diabetic patiENTs). These trials are similarly addressing the high residual risk population with hypertriglyceridemia but also have important differences that may lead to discordant results. REDUCE-IT, which will likely be completed first of the three, is targeting high-risk patients with hypertriglyceridemia without a HDL-C criteria. This trial with 8000 patients treated with either 4 g of IPE or control is trying to replicate the benefits of the JELIS trial in which the subset of patients with triglycerides less than 150 mg/dL and HDL-C less than 40 mg/dL had a dramatic 53% reduction in cardiovascular events in combination with a low dose of pravastatin . The JELIS trial was conducted in Japan, and whether REDUCE-IT can demonstrate a cardiovascular benefit in a population with a much lower baseline of OM3-FA levels and in an era of higher statin dosing with aspirin is eagerly anticipated. The STRENGTH trial has a much larger sample size (n = 13 000) in which OM3-CA 4 g per day is utilized compared to corn oil in a population selected to have a much higher atherogenic residual risk due to a combination of hypertriglyceridemia paired with low HDL-C. In the ACCORD trial, this cohort had about 70% greater cardiovascular event rate compared to the rest of the study population and appeared to benefit with approximately a 8–9 mg/dL decrease in TRL-C. Therefore, the STRENGTH trial is evaluating the population that is most likely to benefit with a similar 8–9 mg/dL decrease in TRL-C but also a shift in small to large LDL-C. The STRENGTH trial also has the added piece of evaluating the effects of much higher EPA and DHA levels, which may be a confounding feature in interpreting the overall results. PROMINENT will recruit an estimated 10 000 high-risk diabetic patients worldwide who have hypertriglyceridemia paired with low HDL-C to determine the effects of treatment with pemafibrate, a potent PPAR-alpha agent on cardiovascular outcomes in a randomized placebo controlled trial. Therefore, this trial will attempt to replicate the ACCORD subgroup findings with fenofibrate utilizing a novel, more potent PPAR-alpha agent and a much larger sample size. Whether this novel agent has the PCSK9 elevating effects or can potentially offset this effect by focusing on the population most likely to benefit is an intriguing hypothesis that will be tested by this large cardiovascular trial. Although these cardiovascular outcome trials are underway, subgroup analyses of data from previous RCTs are suggestive of a reduction in coronary artery disease and ASCVD event rates with lipid altering therapies that lower triglyceride and TRL-C, including statins, fibrates, OM3-FA concentrates, and niacin in patients with triglycerides elevation, particularly if accompanied by a low HDL-C concentration . Although the limitations of such data are acknowledged, clinicians must make treatment decisions while awaiting more definitive results from well-designed large-scale RCTs.
Financial support and sponsorship
Conflicts of interest
Michael H. Davidson was the Chief Medical Officer of Omthera until June of 2015. Omthera Pharmaceuticals clinically developed omega-3 carboxylic acid for FDA approval and was acquired by Astra Zeneca in July, 2013.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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