Fig. 5.1
Chemical structure of ALA, EPA, and DHA as free fatty acids. Note that all bonds present are all cis isomers
ALA is found in both animal and plants [25, 26], while EPA and DHA are found primarily in animal products, with highest concentrations, by far, in fish, such as salmon, sardine, and herring [24]. The role of OM3 FAs in physiology has been well studied. OM3 FAs are incorporated in cellular membranes and organelles, which contribute to cellular structure and function. They are known to be precursors to eicosanoids, which mediate vasodilatory, antiinflammatory, antithrombotic, and antiarrhythmic processes. In addition, there are known effects on gene expression from OM3 FAs [24]. Specifically in regard to lipid metabolism, OM3 FAs are thought to lower triglycerides (TG) through reduced synthesis and release of hepatic VLDL particles into circulation [27]. They also may reduce circulating TG by inhibiting hepatic lipogenesis at the genomic level, leaving less TG available to be incorporated into VLDL particles, and enhanced beta-oxidation of fatty acids [28, 29]. Both EPA and DHA decrease the TG content within VLDL while specifically DHA improves the lipolysis of VLDL and thereby conversion to LDL. Therefore, DHA appears to raise HDL-c and LDL-c more than EPA, particularly in patients with severe hypertriglyceridemia [30, 31]. The mechanisms behind these specific changes are not well understood but may relate to affects on apoC3 metabolism. Genomic studies on apoproteins have also shed light on how OM3 FAs may alter physiology. Genetic variants that carry only one Apo C3 allele were found to have a 40 % lower risk than noncarriers [32]. Apo C3 impairs binding of VLDL to cellular receptors, prolonging residence time in plasma, and resulting in formation of small dense LDL particles [33–36]. In hypertriglyceridemia, the VLDL that is secreted by the liver is enlarged with increased TG content and enhanced apo C3 content relative to apo E. Apo C3 inhibits the apo E-mediated uptake of these TG-rich lipoproteins resulting in elevated VLDL, reduced conversion of VLDL to LDL, and transfer of TG by cholesteryl ester transfer protein from VLDL to LDL and HDL resulting in small dense LDL and HDL particles [37, 38]. Apo C3 also inhibits the effect of apo C2 to stimulate lipoprotein lipase, thus slowing hydrolysis of TG from TG-rich lipoprotein particles and increasing their residence time in circulation [39]. Interventions that lower TG and TRL-C, including fibrates and OM3 FAs, also generally lower the circulating concentration of apo C3 [40–44]. Therefore, the known biochemical effects from OM3 FAs have made them an attractive option to employ into a therapeutic role at the prevention and modification of cardiovascular disease (CVD).
Early epidemiologic studies found a lower rate of cardiovascular related death among populations known to have high dietary fish content [24, 45]. However, later meta-analyses of intervention trials failed to find a benefit for mortality, cardiovascular mortality, or other adverse cardiovascular events [45]. In contrast to this, those with high measured serum concentrations of OM3 FAs are associated with a lower risk of total mortality, sudden cardiac arrest, and nonfatal and fatal myocardial infarction [45].
There is strong biochemical evidence to support the use of OM3 FAs in modification of CVD, although the details regarding employment of these properties have not yet been fully elucidated. Based on this and the epidemiologic studies, there is likely a role for utilization of OM3 FAs in certain patient populations.
Populations for Combinations Therapy
There has been significant controversy regarding the role of OM3 FAs in the prevention and management of CVD. The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults focused primarily on evidence-based review rather than expert opinion, recommending high efficacy statin therapy for at-risk patients and discouraging combination therapy due to lack of evidence for benefits from randomized clinical trials [46]. An ACC/AHA panel did suggest that there is a role for combination therapy in certain high-risk patients with inadequate response to statin therapy or who have issues with statin intolerance, including those with clinical atherosclerotic CVD who are <75 years of age, those with LDL >190 mg/dL, or those with diabetes who are ages 40–75 years [46]. Other guidelines committees from other societies, including International Atherosclerosis Society (IAS), the European Atherosclerosis Society, and American Association of Clinical Endocrinologist (AACE), also recommend judicious use of combination therapy [47–49]. There are no specific recommendations for the use of prescription OM3 FAs from any of these societies. There is also discussion of the use of dietary modification as both recommendations to the general public and as part of the management of patients with severe hypertriglyceridemia (TG ≥500 mg/dL). AACE recommends OM3 FA use as adjunct therapy to niacin or fenofibrates for the treatment of hypertriglyceridemia [49].
Significant numbers of individuals on statin therapy continue to have high residual risk. Combination therapies, including OM3 FAs, appear most appropriate for patients with a high rate of events while taking optimal statin therapy. Although statins reduce the relative risk of cardiovascular events by approximately 20–50 %, depending on the LDL reduction [1], considerable risk of future events remains in some subgroups of patients, including elevated TGs, low HDL, elevated BMI, and a combination thereof [6, 8, 9, 12, 13, 50–55]. One of the strongest predictors of residual risk is hypertriglyceridemia associated with low levels of HDL [8, 9, 50, 51]. Additionally, persistent elevation in ApoB and TG are associated with recurrent cardiovascular events, despite statin therapy [10, 56].
The updated National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III guidelines recommend an optional LDL goal of <70 mg/dL in patients at very high risk, including those with established CVD in conjunction with multiple major risk factors, severe or poorly controlled risk factors, multiple metabolic syndrome components, or acute coronary syndrome [57]. Specifically, NCEP ATP III identified non-HDL as a secondary therapeutic target for individuals with TGs ≥200 mg/dL, where the goal is set 30 mg/dL higher than the LDL goal [57]. Similar recommendation, to treat to goal LDL and non-HDL were present in an Expert Panel report from the National Lipid Association (NLA) for the patient-centered management of dyslipidemia [58], and the International Atherosclerosis Society Global Recommendations for the Management of Dyslipidemia [47]. In a national survey of compliance with NCEP ATP III guidelines, 75 % of patients with coronary heart disease (CHD) met the definition of “very high risk,” yet only 18 % had an LDL <70 mg/dL, and only 4 % had an LDL level <70 mg/dL and a non-HDL level less than 100 mg/dL, when TGs were >200 mg/dL [59]. These data substantiate the use of combination therapy to reduce residual risk in statin optimized patients. Lastly, there exist additional patient populations with familial dyslipidemias and other conditions, which do not necessarily fall within guideline recommendations who may be candidates for OM3 FAs.
Lipid Serologies for the Evaluation of the Patient
Traditionally, guidelines for the management of dyslipidemias have focused on treatment to a specific LDL goal based on medical history. For certain high-risk patients, targets for other values, including non-HDL are also recommended. However, more recent evidence suggests that these traditional ways of estimating residual cardiac risk do not perform optimally. In particular, triglyceride rich lipoprotein-cholesterol (TRL-C), also called “remnant cholesterol,” may be a better measure to utilize when treating to targets and estimating residual cardiovascular risk.
LDL carries ~75 % of the circulating cholesterol in particles other than HDL, making it an attractive treatment target to minimize cardiovascular risk resulting from dyslipidemias. However, there is a growing body of evidence from multiple studies to indicate that TG-rich TRL-C is at least as strongly associated with risk for CHD and other major adverse cardiovascular events as LDL, and, in some studies, even more strongly associated [60–63]. TRL-C includes cholesterol carried by all apo B-containing lipoproteins that are not in the LDL density range, including IDL, VLDL, and chylomicron particles (see Fig. 5.2), the largest portion of which is VLDL. TRL-C is ideally calculated as non-HDL minus LDL, where LDL is directly measured. This is necessary since the Friedewald calculated LDL includes IDL-C. However, the IDL fraction is small and typically allows for an accurate calculation without direct LDL, except in certain patients with conditions such as dysbetalipoproteinemia (prevalence ~0.01–0.1 %) [64], when IDL-C may predominate.
Fig. 5.2
Components of non-HDL and TRL-C
Non-HDL and LDL as Predictors of CHD
An examination of lipoprotein cholesterol as a function of increasing levels of non-fasting TG from population studies conducted in Copenhagen indicated that increased levels of plasma TG were associated with increased levels of remnant cholesterol (R 2 = 0.96, p <0.001), and reduced levels of HDL (R 2 = −045, p <0.001), whereas a positive association between TG and LDL was less pronounced (R 2 = 0.12, p <0.001) [63]. Observation studies indicated that an elevated level of TG is associated with increased risk for CVD [65–68]. However, risk associated with TG elevations are contained entirely within non-HDL and HDL [68].
Population studies have consistently shown that non-HDL is a stronger correlate of CHD event risk than LDL in those with and without hypertriglyceridemia [47, 69–72]. An analysis of data from the Lipid Research Clinics Program Follow-up Study of 2406 men and 2056 women reported that levels of non-HDL and HDL at baseline were significant positive and inverse predictors, respectively, of cardiovascular mortality in both sexes [69]. When analyzed as continuous variables in a multivariate model including non-HDL, LDL, total-C, and HDL and adjusted for age, relative risks (RRs) and 95 % CIs for an increase of 30 mg/dL non-HDL were 1.19 (1.13, 1.26) and 1.15 (1.06, 1.25) in men and women, respectively, and RRs (95 % CIs) associated with a 10 mg/dL increase in HDL were 0.77 (0.69, 0.86) and 0.77 (0.69, 0.88) in men and women, respectively. LDL level was a somewhat weaker predictor of cardiovascular mortality: RR 1.11 (1.02, 1.22) and 1.08 (0.96, 1.22) in men and women, respectively, for each 30 mg/dL increase in LDL. The superiority of non-HDL vs. LDL for major cardiovascular event prediction was also demonstrated in a recent meta-analysis of contemporary statin trials [72]. This analysis used cut-off points of 100 mg/dL for LDL and 130 mg/dL for non-HDL demonstrated that when there was discordance between the two measures (i.e., only one was elevated), risk followed non-HDL more closely than LDL, illustrating that the elevated level of TRL-C was associated with increased CHD risk, even in the presence of low LDL (<100 mg/dL).
TRL-C, Consideration as the Preferred CHD Predictor
Recent data support the hypothesis that TRL-C is not only atherogenic, but may be even more atherogenic than LDL [61, 63, 73]. VLDL remnants are known to cross the endothelial barrier and have been identified in human arteries [74, 75]. Because of their larger size, VLDL particles carry 5–20 times more cholesterol per particle as compared with LDL particles. Importantly, unlike native (unmodified) LDL, remnants can be taken up in an unregulated fashion by scavenger receptors expressed by resident macrophages in the subendothelial space, thus promoting foam cell formation [76, 77]. Chylomicron and VLDL remnants have been shown to rapidly penetrate the arterial wall, and contribute to atherogenesis in animal models [78, 79].
TRL-C (remnant cholesterol) as a risk factor for CHD was examined in two prospective studies and one case control study conducted in Copenhagen Denmark, including 73,514 white subjects of which 11,984 had CHD diagnosed during the follow-up periods. Associations of quintiles of lipoprotein cholesterol with risk for CHD were calculated. The hazard ratio (HR) (95 % CI) for risk for CHD for the first through fifth quintiles for TRL-C were 1.1 (0.8, 1.6), 1.2 (0.9, 1.6), 2.0 (1.5, 2.6), and 2.3 (1.7, 3.1), respectively, and for LDL were 1.0 (0.8, 1.3), 1.2 (0.9, 1.5), 1.3 (1.0, 1.6), and 1.8 (1.4, 2.2), respectively [63]. Thus, comparing the top quintile versus the bottom quintile, higher LDL was associated with an 80 % increase in CHD risk, whereas higher TRL-C was associated with a 130 % increase in CHD risk.
Analyses of several additional sets of data from prospective cohort investigations including the Women’s Health Study (WHS) [80], the Health Professionals Follow-up Study (HPFS) [81], and pooled data from the Nurses Health Study (NHS) and the HPFS also provide support to the relationship between increased TRL-C and increased CVD risk (Table 5.1) [82].
Table 5.1
WHS, HPFS, and Pooled NHS and HPFS: CVD risk according to lipoprotein cholesterol level (quintile 5 compared to quintile 1 as the referent)
Study | LDL HR (95 % CI) | Non-HDL HR (95 % CI) | TG (HR (95 % CI) |
|---|---|---|---|
WHS (n = 27,673) | 1.74 (1.40, 2.16) | 2.52 (1.95, 3.25) | 2.58 (1.95, 3.41) |
HPFS (n = 739 | 2.07 (1.24, 3.45) | 2.75 (1.62, 4.67) | 2.12 (1.21, 3.70) |
Pooled NHS + HPFS (n = 1478) | 1.79 (1.23, 2.64) | 2.53 (1.72, 3.72) | 2.17 (1.51, 3.11) |
Furthermore, genetic evidence demonstrates TRL-C causation of CHD over other traditionally measured factors. A small number of single-nucleotide polymorphisms were shown to be strongly associated with remnant cholesterol, remnant cholesterol/HDL, HDL, and LDL [63]. The numbers of risk alleles for remnant cholesterol (TRL-C) and LDL were more strongly associated with CHD risk than measured lipid levels. Genetic variants associated with decreased HDL alone were not associated with increased risk. Alleles associated with remnant cholesterol were more strongly linked to CHD risk (HR 2.82 [95 % CI 1.92, 4.15] per 1 mmol/L [38.7 mg/dL] increase) than those associated with LDL (HR 1.47 [95 % CI 1.32, 1.63] per 1 mmol/L [38.7 mg/dL] increase). An examination of genomic variants that alter HDL levels indicated that of the 15 variants that alter HDL, just 6 also affect risk for myocardial infarction, and all of these also alter at least one other lipid fraction [32]. These data further support that a shift is needed from the old paradigm for cardiovascular risk assessment that said that total cholesterol (TC) is equal to HDL (good) plus VLDL (uncertain) plus LDL (bad), to a new paradigm in which total cholesterol is equal to HDL (uncertain) plus TRL-C (bad) plus LDL (bad).
Future studies should consider utilization of TRL-C in study coordination. There are multiple lines of evidence from various study types to support the causality for TRL-C and CHD/CVD risk, including results from randomized control trials, but the evidence is limited by the designs of the studies conducted to date. The preferred CVD outcomes study design would include exclusive or predominant enrollment of subjects with elevated TRL-C (e.g., high to very high TG) and use an intervention that produces a substantial reduction in TRL-C.
Implications of the Evidence for a Causal Role of VLDL Elevation in Promoting CVD Risk
1.
TRL-C is at least as strongly associated with CVD event risk per mg/dL as is LDL, which explains the superiority of non-HDL over LDL as a predictor of cardiovascular event risk.
2.
Elevated non-HDL due to increased TRL-C is likely to be an important source of residual risk in a subgroup of statin-treated in patients with well-controlled LDL.
3.
Because TRL-C is at least as atherogenic as LDL, non-HDL should be the preferred target of therapy.
Therapy with Omega-3 Fatty Acids
Summary of Evidence for Use
Early secondary prevention studies suggested that supplementation with daily OM3 FAs improved lipid profiles and reduced cardiac events for those with and without a history of CHD. As previously mentioned, dietary supplementation with fatty fish was found to assist in the prevention of death related to CHD in the Diet and Reinfarction Trial (DART) [83]. Initial analysis of Omacor (Lovaza), a mix of EPA and DHA, in a population of patients with hypertriglyceridemia showed significant reduction in TG by 45 %, cholesterol by 15 %, VLDL by 32 %, and an increase in HDL by 13 % and LDL by 31 % [84]. The GISSI trial was next to evaluate the efficacy of direct OM3 FA supplementation on cardiovascular events, which found that supplementation of patients ≤3 months post-myocardial infarction with 1 g of a combination of EPA and DHA (ratio 1:2) ethyl esters significantly reduced death and cardiovascular death [85]. These findings were further solidified when the Japan EPA Lipid Intervention Study (JELIS) demonstrated addition of EPA to statin therapy in those with or without prior myocardial infarction led to a 19 % relative reduction in major cardiac events with a 25 % decrease in LDL cholesterol [13].
Later analyses did not support the benefit from supplementation of OM3 FAs. The Alpha Omega Trial investigated dietary supplementation with ALA and combination EPA-DHA within margarines. The patients were found to have ingested 226 mg of EPA with 150 mg of DHA and/or 1.9 g of ALA, which did not show significant reductions in major cardiovascular events, although women assigned to the ALA treatment arm had a reduction in cardiovascular events that approached significance (HR 0.73; 95 % 0.51–1.03) [86]. Next, in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN), supplementation with 1 g Lovaza (465 mg EPA; 375 mg DHA) in high-risk patients did not find a significant difference in cardiac events, but did find a 14.5 mg/dL decrease in TG without significant changes in other lipids [87]. Then, the Risk and Prevention Study Collaborative Group, patients with multiple cardiovascular risk factors or known atherosclerosis were assigned to 1 g of OM3 FA ethyl esters (containing EPA and DHA in ratio from 0.9:1 to 1.5:1) versus olive oil [88], which resulted in no significant findings in relation to cardiovascular mortality and morbidity. In each of these trials, patients were assigned to relatively low levels of OM3 FA supplementation, which did not lower serum TG, and although higher risk groups were selected, there was no specific selection of the high-risk patients who may have conferred a benefit. In fact, the one aforementioned group that approached near-efficacy was the group of women who had the highest OM3 FA intake at ~2 g (of ALA) per day.
Several design issues should be considered in evaluating the clinical importance of the cardiovascular outcomes trials conducted to date with OM3 FA interventions. This includes the use of low dosages of OM3 FAs that had modest effects on TG and VLDL concentrations. For example, in a large 2012 meta-analysis of OM3 FA trials to date, the median (interquartile range limits) dosage was 1.0 (0.5–1.8) g/day EPA and/or DHA, mostly as ethyl esters [89]. JELIS was the only pharmaceutical OM3 intervention trial to examine cardiovascular outcomes in which a dosage was used that is in the range required to appreciably lower TG and VLDL levels (1.8 g/day EPA ethyl esters) [13]. These studies were not conducted in patients who would be expected to have the greatest potential to benefit from TG and VLDL lowering therapy (i.e., patients with high TG or high TG and low HDL). Thus, data are needed to prospectively evaluate the potential cardiovascular benefits of using OM3 FAs as a lipid-altering intervention at a therapeutic dosage level in patients with elevated TG.
These observations led to additional analyses, which selected the highest risk groups in attempts to find potential patients who may benefit from OM3 FA supplementation. Post hoc analysis did suggest significant benefit for diabetic patients with a history of an MI and for patients who were not on statin therapy [90]. Other studies in patients already on statin therapy demonstrate improvement in lipid serologies. The aforementioned JELIS trial already elucidated some initial possible benefits of adding OM3 FAs to statin therapy. In other trials, OM3 FAs have been found to further reduce LDL 13–24 % and TG 27–30 % in patients on pravastatin 40 mg/day [91] or simvastatin 20 mg/day [92]. When added to simvastatin for patients with TG ≥200 and <500 mg/dL, 4 g/day of Lovaza was found to significantly decrease TG 29.5 %, VLDL 27.5 %, TC/HDL ratio 9.6 %, and raise HDL 3.4 % [93].
More recent trials of highly refined OM3 FAs (Vascepa and Epanova) have been shown to effectively treat hypertriglyceridemia and appear to have no HDL lowering effects, which may be augmented by high potency statin use [94–97]. The MARINE trial also investigated patients with TG ≥500 and <2000 mg/dL, but with or without background statin therapy, to highly purified EPA ethyl ester (AMR101 [Vascepa]) without DHA. Vascepa 4 g/day was found to significantly reduce serum TG by 27 % compared to 10 % increase with mineral oil with also reduction in non-HDL (8 % reduction with 4 g/day compared to a 8 % increase with mineral oil), apolipoprotein B, lipoprotein associated phospholipase A1, VLDL, and TC [95]. The ANCHOR trial also evaluated Vascepa, but in patients with TG ≥200 to <500 with LDL >40 and <100 mg/dL while on statin therapy. Significant placebo-adjusted reductions in TG (21.5 % with 4 g/day and 10.1 % for 2 g/day), non-HDL (13.6 % with 4 g/day and 5.5 % with 2 g/day), VLDL (26.5 % with 4 g/day and 11.3 % with 2 g/day), LDL, TC, apoB, lipoprotein-associated phospholipase A2, and high-sensitivity C-reactive protein were observed over a 12-week period [94].
A novel combination of EPA and DHA as carboxylic acid (free fatty acid), rather than ethyl esters, Epanova, has also been evaluated (Fig. 5.3). The benefit of the OM3 carboxylic acid form is an up to four-fold greater bioavailability compared to currently available OM3 ethyl ester drugs [98, 99]. This is because the free fatty acid form avoids the need for hydrolysis by dietary fat stimulated pancreatic lipases, which may have significant clinical implications since those with severe hypertriglyceridemia are recommended to follow a low-fat diet [48, 49, 98, 99]. The EVOLVE trial found that patients with TG ≥500 and <2000 mg/dL assigned to higher dose EPA and DHA as free fatty acids at a total of 2–4 g/day versus placebo in patients with TG ≥500 and <2000 mg/dL. Fasting serum TGs decrease by 25.5–30.9 % from baseline with also having reductions in non-HDL (6.9–9.6 % decline versus 2.5 % increase in placebo group), TC to HDL ratio, VLDL, TRL-C, apolipoprotein C3, lipoprotein-associated phospholipase A2, and arachidonic acid [96]. The ESPIRIT trial followed, which investigated Epanova in patients with fasting TG levels ≥200 to <500 mg/dL, with 2 or 4 g/day of Epanova versus olive oil. This trial demonstrated significant reduction in non-HDL levels of 3.9 % (2 g/day) to 6.9 % (4 g/day) versus 0.9 % (control), TG levels (14.6 % (2 g/day) to 20.6 % (4 g/day) reduction versus 5.9 % (control)), increased LDL with 2 g/day dosing only (4.6 % versus 1.1 % (control)), and decreased TC, VLDL, and for higher dosages (4 g/day) also finding decreased TC/HDL ratio, apo-AI, and ApoB [97]. Based on these results, Epanova was approved by the FDA for the treatment of severe hypertriglyceridemia with either a 2 or 4-g daily dose without regards to meals.
Fig. 5.3
EPA fatty acids shown as the Ethyl Ester compared to Carboxylic Acid formulations
In summary, there is emerging evidence for the use of OM3 FAs. There is a clear benefit in the reduction of TGs with the supplementation of OM3 FAs in patients with severe hypertriglyceridemia, and perhaps certain subgroups with hypertriglyceridemia where benefit of adding this therapy has yet to be completely elucidated. One criticism of many of these studies is that the dose of OM3 FAs were particularly small and perhaps the benefits were not observed due to not obtaining treatment range dosing.
Ongoing Clinical Trials
Despite the promising effects at reduction of TG and non-HDL, evidence still lacks for overt reduction of cardiovascular events with OM3 FA supplementation. However, there are ongoing trials, which seek to address whether new high-potency OM3 FAs can further reduce cardiovascular events beyond TG lowering in patients with hypertriglyceridemia on statin therapy.
The REDUCE-IT Trial is a phase-3 study of ~8000 patients with high baseline TG (≥150 mg/dL initially, then later increased to ≥200) and at least one other cardiac risk factor who are being treated with Vascepa versus control (mineral oil) as add-on to statin therapy. Outcomes being measured include composite endpoint of cardiovascular death, MI, stroke, coronary revascularization, and hospitalization for unstable angina. Estimated completion data is December 2017 [100, 101].
The STRENGTH Trial is a phase-3 study to investigate the effectiveness of adding Epanova to statin monotherapy for lowering major adverse cardiovascular events versus adding placebo, corn oil, to statin therapy. This study will include ~13,000 subjects with TG ≥200 and <500 mg/dL with low HDL (<40 mg/dL for men and <45 mg/dL for women) despite being on optimal or maximally tolerated statin dose, and at high risk for CVD. Outcome being measures is time to the first occurrence of any major adverse cardiac event (cardiovascular death, nonfatal MI, nonfatal stroke, emergent/elective coronary revascularization, or hospitalization for unstable angina). Estimated completion date is June 2019 [102].
Side Effects/Tolerance
In general, OM3 FA supplements are well tolerated with low side effects. There have been rare reports of interaction with anticoagulants, and periodic monitoring has been suggested. The ACC/AHA guidelines recommend that if OM3 FAs are utilized that it is “reasonable to evaluate the patient for gastrointestinal disturbances, skin changes, and bleeding” [46].
Lovaza – Side effects include dyspepsia, eructation, rash, taste perversion, back pain, infection, flu syndrome, and other pain. Other less common side effects have been reported in post-marketing surveillance, but are rare [103].
Vascepa – Side effects include arthralgias and elevated fasting glucose. Evidence of increase risk of bleeding occurred in higher dose treatment (4 g/day), with 2 cases of CNS bleeding. Along with other OM3 FAs, it is recommended that patients taking Vascepa and drugs affecting coagulation be periodically monitored [104].
Epanova – Side effects gastrointestinal disorders, with higher incidences of diarrhea, nausea, eructation, abdominal pain, flatulence, and dysgeusia [97, 105]. In patients with chronic gastrointestinal diseases, there were reports of abdominal distension, constipation, vomiting, fatigue, nasopharyngitis, arthralgia, and dysgeusia [105].
Consideration Versus Fenofibrates as Add-On Therapy
There exist multiple options for add-on therapy to statins in those without optimal risk minimization. In particular, evidence suggests OM3 FA and fenofibrates as potential beneficial options. Careful consideration should be made when deciding the next add on therapy, particularly in the current era where data to support such indications are not robust. When comparing fenofibrates to OM3 FAs, one should consider side effects, their effect on non-HDL and on LDL, and potential mortality benefit.
Regarding side effects not all fibrates are well tolerated when added to statin. In particular, gemfibrozil has been found to have a particularly high risk for development of myopathy [106]. Regarding fenofibrate, although not causing increased rates of muscle-related adverse events, addition of fenofibrate to statin therapy has higher liver and kidney-related adverse events [107].
In the ACCORD trial, which tested fenofibrate + statin therapy effect on lipid serologies and cardiovascular events. Fenofibrate with statin did not demonstrate the same rate of myopathy as seen with Gemfibrozil. In this trial, patients with TG ≥204 mg/dL and HDL ≤34 mg/dL were found to have a placebo correct reduction in VLDL of 8.6 mg/dL with increase in LDL of 9 mg/dL. The cardiovascular event rate was decreased, with a HR of 0.69 (p = 0.03) [8]. In a similar set of patients, the ESPIRIT trial also showed placebo corrected reduction in VLDL of 7.3 mg/dL, non-HDL of 8.5 mg/dL, with minimal increase in LDL of 0.5 mg/dL. Since there is minimal effect on LDL and nearly the same effect on VLDL, OM3 FA will likely confer the same, if not better outcomes based on change in lipid profiles. What is more, OM3 FAs have a better tolerability profile.
Role in Specific Patient Populations
Statin Intolerance
OM3 FA supplementation in those who do not tolerate statins is a sensible option. Without any statin the patient with dyslipidemia is at considerable risk for cardiovascular combinations. As previously mentioned, initial trials before the statin age have shown that OM3 FA not only improve lipid profiles [84], but also decrease rate of death and cardiovascular death [85].
Familial Dyslipidemias
There are few studies to assess the efficacy of OM3s on specific familial conditions, but the few that exist suggest a potential benefit. One early study of 9 patients with familial combined hyperlipidemia, supplemented with 3.0–4.5 g/day combination EPA/DHA OM3 FAs lowered VLDL TG 42–55 %, VLDL 41–47 %, VLDL Apo-B 40–56 % (for lower and higher doses, respectively), with no overall change in LDL, although 4 patients experienced a 19 % dose dependent increase in LDL [108]. In one study, supplementation with Lovaza (4 g/day) resulted in lower of TG 21 %, VLDL 29 %, with no change in HDL or TC, and an increase in LDL by 21 % compared to placebo, suggesting a benefit from addition of OM3 FAs [109]. Other data present from additional case reports suggests that there may be additional uses for OM3 FA supplementation. In one patient with lipoprotein lipase deficiency, supplementation with 4–6 g/day OM3 FAs (EPA/DHA mix, ratio 1.4:1) was found to normalize fasting lipid profiles [110]. Similarly another case of chylomicronemia in 12 patients found that 12 weeks of OM3 FA supplementation (first with 2.16 g grams, titrated to 4.32 g for the last 8 weeks) decreased TG by 45 %, with decreases within the chylomicron fraction of TG, VLDL, and TC [111].
Conclusion
There is clear scientific understanding of how OM3 FAs integrate with physiology. These mechanisms can be exploited for the modification of disease. Current studies on how to best take advantage of this implicate that OM3 FAs alter the course of CVD both for prevention of adverse cardiovascular outcomes and treatment of derangements in lipid serologies. Current guidelines and recommendations support their regular integration into the diet and supplementation for those with severe hypertriglyceridemia as adjunct therapy.
Emerging data suggests that OM3 FAs may have implications in specific subpopulations. In particular, patients with elevated triglycerides may benefit from supplementation as combination therapy to statins and lifestyle changes, especially those with TGs ≥500 mg/dL, and perhaps pending results of ongoing trials, those with TGs ≥200 mg/dL and <500 mg/dL. Additional roles for OM3 FAs lie in certain subgroups with specific familial dyslipidemias and those who do not tolerate statin therapy.
In conclusion, an elevated level of TG is associated with increased CHD/CVD risk, and the risk associated with elevated TG is completely captured by non-HDL (which includes LDL-C and TG-rich lipoprotein cholesterol [typically estimated as TRL-C]) and HDL-C. Non-HDL, which reflects TG-rich lipoprotein cholesterol in addition to LDL, is at least as strong, and possibly stronger, than LDL as a predictor of CVD risk in patients with hypertriglyceridemia.
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