Your notion that L raises LDL-C, is mitigated by increasing the particle size is not true.. The general rule which L follows is that gents which raise LDL-C also decrease the particle size and increase LDL-P...the LDL-P particle count being a better predictor of CVD event risk than LDL-C. --JL
Well, it's not true that n-3 increases LDL particle size and decreases LDL-P concentration. Actually data show the opposite occurs, as I already proved, but will do so again. I'll also put together other proofs from other posts of mine into this one, as they are getting rather scattered.
This study shows doing with n-3 (similar to Lovaza, containing large amounts of DHA) decreased LDL-P, and increased LDL size:
Men and women with non-HDL-C >160 mg/dL and TG 250-599 mg/dL, while taking no lipid-altering drugs, received double-blind 4 g/d POM3 (n = 118) or placebo (n = 119) with open-label atorvastatin 10 mg/d for 8 weeks, followed by escalation to 20 mg/d atorvastatin for 4 weeks, then 40 mg/d atorvastatin for 4 weeks.
Results
Total low-density lipoprotein particle (LDL-P) concentration decreased significantly from baseline, and the reductions did not differ between the POM3 and placebo groups (-659.7 vs -624.4 nmol/L, P = .181). With POM3, compared with placebo, small LDL-P concentration decreased (P = .026), large LDL-P concentration increased (P < .001), mean LDL-P size increased (P = .001), a larger fraction of subjects switched from LDL subclass pattern B to A, and Apo CIII and lipoprotein-associated phospholipase A2 levels were reduced (P < .001). The incremental effects of POM3 were similar across atorvastatin doses for most variables.
And if that sample was just a little larger, the reduction in total LDL-P concentration of -659.7 with n-3 vs -624.4 with statins alone, would have been significant.
The thing about DHA that is not true with EPA alone is that DHA blocks LDL synthesis. DHA is of course very abundant in many fish species, and especially in fatty fish, and even more so than EPA:
The occasional increase in LDL concentrations that occurs after VLDL and triacylglycerol concentrations are greatly lowered by fish oil is similar to the increase in LDL that occurs after the drug gemfibrozil is given. LDL synthesis and plasma LDL concentrations were reduced after large doses of fish oil were given (23). In contrast with the n-6 fatty acid–rich vegetable oils that lower HDL concentrations, fish oil does not decrease HDL concentrations (19).
This was confirmed in a dietary study of high EPA+DHA fish intake. And very high doses of EPA+DHA in diet can have a profound effect on LDL-P concentration, which ends up finally even lowering LDL-C:
The control diet contained predominantly saturated and monounsaturated fatty acids, whereas the fish-oil diet contained 24 gm of omega-3 fatty acids per day. The total fat and cholesterol content of the two diets were similar for each subject. Total and LDL cholesterol levels decreased from 162 +/- 26 mg/dl and 103 +/- 27 mg/dl on the control diet to 124 +/- 26 mg/dl and 82 +/- 27 mg/dl on the omega-3-rich diet. Triglyceride levels fell from 91 +/- 34 mg/dl to 52 +/- 19 mg/dl.
Kinetic studies of 125I-LDL metabolism disclosed a significantly lower rate of synthesis of LDL apoprotein B on the omega-3-rich diet (9.5 +/- 1.3 mg/kg/day) as compared to the control diet (13.6 +/- 3.7 mg/kg/day; p less than 0.05). In contrast, the fractional catabolic rate was similar on both diets.
We conclude that dietary omega-3 fatty acids lower plasma LDL levels in normal human subjects by reducing the rate of synthesis of apoprotein B.
In patients with hyperlipidemia, omega 3 fatty acids decrease low-density-lipoprotein (LDL) cholesterol if the saturated fatty acid content is decreased, otherwise there is a slight increase, but at high doses (32 g) they lower LDL cholesterol.
LDL particle size increased significantly with DHA supplementation, a result that might be expected to contribute to a reduction in atherogenic risk. Ours is the first report showing a specific effect of DHA on LDL particle size, although others have shown increased LDL particle size after n-3 fatty acid supplementation (45, 46).
Small, dense LDL particles are associated with an increased risk of coronary artery disease (47) and an increase in plasma triacylglycerol concentrations (48). Both triacylglycerols and HDL cholesterol are major determinants of LDL particle size (49), partly because the exchange of triacylglycerols from VLDL for cholesterol ester in LDL, which is mediated by cholesteryl ester transfer protein (CETP). It is possible that as serum triacylglycerols decrease after n-3 fatty acid supplementation, fewer triacylglycerols are transferred to LDL by CETP, reducing the formation of triacyglycerol-enriched LDL, which minimizes the opportunity for lipoprotein lipase to convert large LDL particles to small LDL particles. This hypothesis is supported by reports of reduced CETP activity after n-3 fatty acid supplementation (41).
Given the similarity in triacylglycerol lowering by EPA and DHA, our results may be related to a more pronounced effect of DHA on CETP activity.
So we see that EPA+DHA, as is found in nature, may raise LDL-C (amount of cholesterol in LDL particles) somewhat (except at very high doses), but that is in conjunction with LDL size increasing (anti-atherogenic) and LDL-P concentration decreasing (also anti-atherogenic).
As also stated, LDL-P concentration and LDL particle size are much better correlated with MACE risk than LDL-C:
METHODS:
Concentrations of LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) were measured chemically and LDL particle number (LDL-P) and VLDL particle number (VLDL-P) were measured by nuclear magnetic resonance (NMR) in 3066 middle-aged white participants (53% women) without CVD in the Framingham Offspring cohort. The main outcome measure was incidence of first CVD event.
RESULTS:
At baseline, the cholesterol content per LDL particle was negatively associated with triglycerides and positively associated with LDL-C. On follow-up (median 14.8 yrs), 265 men and 266 women experienced a CVD event. In multivariable models adjusting for non-lipid CVD risk factors, LDL-P was related more strongly to future CVD in both sexes than LDL-C or non-HDL-C. Subjects with a low level of LDL-P (<25(th) percentile) had a lower CVD event rate (59 events per 1000 person-years) than those with an equivalently low level of LDL-C or non-HDL-C (81 and 74 events per 1000 person-years, respectively).
CONCLUSIONS:
In a large community-based sample, LDL-P was a more sensitive indicator of low CVD risk than either LDL-C or non-HDL-C, suggesting a potential clinical role for LDL-P as a goal of LDL management.
And as also evidenced in the above study, non-HDL-C is better correlated with MACE than LDL-C:
Those with diabetes had a 200% higher RR than those without diabetes. In a multivariate model, CHD risk in those with diabetes did not increase with increasing LDL, whereas it did increase with increasing non-HDL: RR (95% confidence interval) for group 1: 5.7 (2.0-16.8); group 2: 5.7 (1.6-20.7); group 3: 7.2 (2.6-19.8); and group 4: 7.1 (3.7-13.6).
LDL-C alone is the worst of the three lipid indicators of MACE risk with LDL-P concentration and LDL size the most important.
I hope that helps the board understand that the small increase in LDL-C seen in lipid panels when DHA is taken with EPA is actually a positive sign that LDL-P are larger than they were (and thus less atherogenic). LDL-P size increases with EPA+DHA dosing. LDL-P concentration goes down with EPA+DHA dosing. This does not occur when EPA is isolated and dosed without DHA (and other fatty acids present in fish oil). These co-exist in nature after all. And many centuries of Japanese consuming high amounts of DHA has only seemed to help them.
Please give us links to EPA's action re oxLDL...being harmful...go ahead I dare you... --JL
Okay:
There is evidence that long chain n-3 PUFA (such as from fish oils) provide atheroprotection through, in part, changes in macrophage function although it has not been fully determined whether these n-3 PUFA target cellular mechanisms that control macrophage foam cell formation. Therefore, we investigated whether the n-3 PUFA, EPA and DHA, modulate modified low-density lipoprotein (LDL) uptake by human macrophages. The uptake of fluorophore labeled acetylated LDL (AcLDL) and/or oxidized LDL (OxLDL) by THP-1 macrophages and primary human monocyte-derived macrophages were measured by flow cytometry following co-incubation with EPA or DHA in vitro. DHA inhibited both AcLDL and OxLDL uptake in human macrophages whilst EPA reduced AcLDL and increased OxLDL uptake.
EPA did inhibit uptake of other modified forms of LDL, but not oxLDL--and in fact increased its uptake. That's what matters more than concentration of oxLDL in blood serum.
EPA...as this article clearly points out is beneficial and not detrimental as suggested by Py...
"Presenting the results of the laboratory study here at the National Lipid Association (NLA) 2011 Scientific Sessions, senior investigator Dr Preston Mason (Brigham and Women's Hospital, Boston, MA) said that EPA is an inhibitor of lipid oxidation at normal and elevated cholesterol levels in the presence and absence of DHA, while DHA seems to have no real effect on lipid peroxidation.
We know that EPA and DHA have different effects on LDL-cholesterol levels," Mason told heartwire . "One of the things that affect LDL clearance is its oxidative state. Oxidized LDL is not cleared. One of the concepts is that EPA might preferentially prevent LDL oxidation, so even though it's not affecting its synthesis, it would help its clearance."
--JL
Well, once again, an in vitro experiment that suggests EPA can prevent lipid oxidation (not the same as oxidation of LDL) is nice and all. But what do in vivo studies show? They show that higher doses of n-3 increase markers of lipid peroxidation. And when I recall that EPA showed increased oxLDL uptake by macrophages (while DHA inhibited the same), I consider that fatty acid to be implicated in the phenomenon.
This goes along with another quote of yours, so I'll paste it here:
TBARS do not measure CVD risk accurately...So what if they lower Vit E. If you think Vit E is going to protect you fron CVD events...Well go ahead.. --JL
Well actually both are quite implicated in lipid peroxidation, atherosclerosis and risk of MACE:
Another method of determining oxidative stress is to measure the disappearance of antioxidants, such as alpha-tocopherol [vitamin E], from the blood. Because the majority of plasma tocopherols are found in plasma lipids, which have been shown to decrease in the critically ill, any measure of plasma tocopherols in the critically ill population should be indexed to total cholesterol.
And what happens when we leave the petri dish (in vitro) behind and look directly at what "high" doses of n-3 (5.1 g/d) does in subjects themselves (in vivo)? TBARS went up, while serum vit E went down (both atherogenic), and other mixed benefits:
Our hypothesis was that n-3 FA supplementation might improve the endothelial dysfunctional state in the present population with advanced CHD, and this might be evaluated by the presently measured soluble markers. The finding of lower values of the hemostatic markers vWF, and sTM in group I at baseline, and the significant reductions in sTM and t-PAag in group II during the study period would fit this hypothesis.
However, the finding of higher values of the inflammatory markers sE-sel and sVCAM-1 in group I at baseline, and the significant increasing change in these markers in group II during the study period, was unexpected. All over, the findings seem to indicate that supplementation with highly concentrated n-3 FA to patients with coronary atherosclerotic disease decreases the hemostatic activity of the endothelium, whereas the inflammatory activity might be increased.
Concerning the changes in t-PAag, this may possibly be linked to the simultaneous changes in triglycerides. Triglycerides have been demonstrated to stimulate cultured endothelial cells to release plasminogen activator inhibitor-1 (PAI-1).22 Thus, a reduction in triglycerides may lead to reduced PAI-1 secretion. It is also suggested that in steady-state conditions t-PAag mainly reflects the level of PAI-1,23 as the t-PAag method used determines both t-PA and PAI-1. Accordingly, the t-PAag reductions obtained during n-3 FA supplementation might reflect reduced endothelial secretion of PAI-1 along with the reduction in triglycerides.
Concerning the markers of inflammation, our results are not in accordance with some previously published studies. However, it should be emphasized that our study was performed as a clinical trial in patients with atherosclerotic disease and not in isolated cells. We are not aware of previous studies on soluble inflammatory factors that have been performed in a population readily comparable with ours. However, similar results, that is, an increase in sE-sel and sVCAM-1 after supplementation with n-3 FA, were recently described by Seljeflot et al26 in a population of healthy individuals at high risk for atherosclerotic disease states.
Finally, moderate beneficial effects with n-3 FA have been demonstrated in different inflammatory diseases such as rheumatoid arthritis,29 30 and clinical benefit of n-3 FA has also been reported in patients with psoriasis.31
On the other hand, Blok et al32 reported in a prospective trial that fish oil supplementation did not affect the concentrations of circulating cytokines. Furthermore, they found the ex vivo production of cytokines (interleukin-Iß, tumor necrosis factor-a, and interleukin-Ra), after endotoxin stimulation of whole blood, to be significantly increased during fish oil supplementation. However, the observed increase was not significantly different from that in the placebo group.
The reason for the apparent discrepancy is not clear. However, it is well known that polyunsaturated fatty acids are prone to peroxidation and that generated free radicals and oxidized LDL may both be cytotoxic.33 Various authors have suggested the possible deleterious effects of n-3 FA supplementation because of their increased susceptibility to oxidation,34 35 36 although contradictory results have been reported.15
This could also be discussed along with the decreased levels of vitamin E after n-3 FA supplementation encountered in the present study. This finding is in accordance with what we have recently reported in another study26 and also with the results from Hau et al,37 suggesting a consumption of antioxidants caused by an increased level of oxidation after n-3 FA supplementation.
Increased TBARS values after long-term supplementation with n-3 FA, as evidenced by the differences between the groups at baseline and the differences in changes between the groups during the study period, further supports the hypothesis of increased peroxidation.
In conclusion, we could demonstrate that high-dosage n-3 FA supplementation decreases circulating t-PAag and sTM and increases sE-sel and sVCAM-1 in blood from patients with CHD. In addition to reduced levels of hemostatic markers of atherosclerosis, these results might indicate a proinflammatory response that could be adverse, possibly brought about by an increased peroxidation as demonstrated by a consumption of vitamin E and increased TBARS.
This kind of phenomenon is shown in other studies as well.
"High" dose EPA causes marked increase in serum levels of theobarbituric acid reactive substances (TBARS), and possibly MDA, which are predictive of greater frequency of cardiovascular events.
Let's take a look at a study that tested a mostly EPA (2.0g/d) dose of n-3 and measured various oxidation markers, including TBARS:
Background: Although the replacement of dietary saturated fat with unsaturated fat has been advocated to reduce the risk of cardiovascular disease, diets high in polyunsaturated fatty acids (PUFAs) could increase lipid peroxidation, potentially contributing to the pathology of atherosclerosis.
Objective: The objective of this study was to examine indexes of in vivo lipid peroxidation, including free F2-isoprostanes, malondialdehyde (MDA), and thiobarbituric acid reacting substances (TBARS), in the plasma of postmenopausal women taking dietary oil supplements rich in oleate, linoleate, and both eicosapentaenoic acid and docosahexaenoic acid.
Design: Fifteen postmenopausal women took 15 g sunflower oil/d, providing 12.3 g oleate/d; safflower oil, providing 10.5 g linoleate/d; and fish oil, providing 2.0 g EPA/d and 1.4 g DHA/d in a 3-treatment crossover trial.
Results: Plasma free F2-isoprostane concentrations were lower after fish-oil supplementation than after sunflower-oil supplementation (P = 0.003). When plasma free F2-isoprostane concentrations were normalized to plasma arachidonic acid concentrations, significant differences among the supplements were eliminated. Plasma MDA concentrations were lower after fish-oil supplementation than after sunflower-oil supplementation (P = 0.04), whereas plasma TBARS were higher after fish-oil supplementation than after sunflower oil (P = 0.003) and safflower oil (P = 0.001) supplementation. When plasma MDA concentrations were normalized to plasma PUFA concentrations, significant differences were eliminated, but TBARS remained higher after fish-oil supplementation than after sunflower oil (P = 0.01) and safflower-oil (P = 0.0003) supplementation.
Net net, large jump in TBARS. And notice the author's mention of implication between these markers and the pathology of atherosclerosis.
Here's a study that supports this claim:
The objective of this study was to test the predictive value of an oxidative stress biomarker in 634 patients from the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT).
During the three-year study, there were 51 major vascular events such as fatal/nonfatal myocardial infarction, 149 hospitalizations for nonfatal vascular events, and 139 patients underwent a major vascular procedure. At baseline, patients with TBARS levels in the highest quartile had a relative risk (RR) of 3.30 (95% confidence interval [CI] 1.47 to 7.42; p = 0.038) for major vascular events, RR of 4.10 (95% CI 2.55 to 6.60; p < 0.0001) for nonfatal vascular events, and RR of 3.84 (95% CI 2.56 to 5.76; p < 0.0001) for major vascular procedures. The effect of TBARS on events and procedures was also seen in a multivariate model adjusted for inflammatory markers (C-reactive protein, soluble intercellular adhesion molecule-1, interleukin-6), and other risk factors (age, low-density lipoprotein, high-density lipoprotein, total cholesterol, triglycerides, body mass index, and blood pressure). This analysis showed an independent effect of TBARS on major vascular events (p = 0.0149), nonfatal vascular events (p < 0.0001), major vascular procedures (p < 0.001), and all vascular events and procedures (p < 0.0001).
A massive jump in risk, and a very significant finding (extremely low p-values).
It seems to occur mostly from higher dose n-3. 1g/d doesn't seem to cause much of this.
Here's a straight up example of EPA causing TBARS to elevate:
Eicosapentaenoic acid (EPA) is one of the major dietary polyunsaturated fatty acids and induces apoptosis in several cancer cells. In this study, the EPA induced lipid peroxidation and response of antioxidative enzymes have been investigated in rat pheochromocytoma PC12 cells to elucidate the mechanisms of apoptosis induced by the polyunsaturated fatty acid EPA. We have analyzed superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities and glutathione (GSH) contents in PC12 cells after exposure to different concentrations of EPA. Lipid peroxidation was shown to increase in the presence of EPA as an indication of the oxidative damage. Lipid peroxidation was enhanced by EPA in a dose-dependent manner, and the loss of cell viability was partially reversed by vitamin E. In the case of antioxidant enzyme activities, SOD and GPX activities and GSH contents increased significantly at 50 micromol/L EPA and were respectively 2.41-fold (p < 0.01), 3.49-fold (p < 0.05), and 1.43-fold (p < 0.05) higher than controls. The CAT activity at 10 micromol/L had the highest value and was increased by 25.83% (p < 0.05) compared to control. The results suggest that in PC12 cells the mechanism of apoptosis induced by EPA may be partly due to lipid peroxidation.
Net net, this is just more evidence that the potential beneficial effects of EPA may be outweighed by deleterious side-effects when the dose is much increased from 1g/d to 4g/d.
Getting back to DHA vs EPA, and why losing DHA is probably a bad idea--EPA dosing at 4g/d leads to a significant reduction in HDL-C, whereas DHA at 2 and 4g/d tends to raise HDL-C, and especially HDL2. That raises the risk of MACE with EPA dosing at 4g/d, and loses a benefit from DHA concurrently (**note that Japanese in JELIS were getting lots of DHA in their diet already, which may have counter-balanced this negative phenomenon from high EPA-alone dosing. Although also they received only 1.8g/d EPA, which has a mild effect on HDL).
To determine if the ratio of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids in fish oil had an effect on plasma lipid responses, we randomly fed eight normolipidemic men three 36%-fat diets containing primarily butter, EPA-rich pollock oil, or DHA-rich tuna or salmon-blend oils. Plasma EPA and DHA reflected the amounts in the diets. Compared with values for the butter diet, very-low-density lipoprotein (VLDL) triglycerides decreased equally (71-78%) with all diets; low-density lipoprotein (LDL) cholesterol (LDL-C) and apolipoprotein B decreased 26% and 13%, respectively, on the tuna and salmon-blend oil [DHA:EPA of 2:1] but did not change (-1%) and increased 19% with the pollock diet [high EPA]; high-density lipoprotein cholesterol (HDL-C) and lipoproteins A-I and A-II decreased with all diets but more with the pollock diet than with the tuna and salmon diets. The 23-31% decrease in total cholesterol on the tuna and salmon diets resulted mostly from decreased LDL-C whereas the 16% decrease on pollock oil resulted mostly from a decrease in HDL-C.
DHA raises HDL, and especially HDL2, which is cardio protective. Meanwhile EPA-alone reduces HDL-C and especially HDL3, which elevates risk of MACE:
Results: Fifty-six men aged 48.8 ± 1.1 y completed the study. Relative to those in the olive oil group, triacylglycerols fell by 0.45 ± 0.15 mmol/L (˜20%; P = 0.003) in the DHA group and by 0.37 ± 0.14 mmol/L (˜18%; P = 0.012) in the EPA group. Neither EPA nor DHA had any effect on total cholesterol. LDL, HDL, and HDL2 cholesterol were not affected significantly by EPA, but HDL3 cholesterol decreased significantly (6.7%; P = 0.032). Although HDL cholesterol was not significantly increased by DHA (3.1%), HDL2 cholesterol increased by ˜29% (P = 0.004). DHA increased LDL cholesterol by 8% (P = 0.019). Adjusted LDL particle size increased by 0.25 ± 0.08 nm (P = 0.002) with DHA but not with EPA.
It has been suggested that serum HDL cholesterol is better maintained with DHA-enriched than with EPA-enriched oils (38). The present data and previous findings (19) support this hypothesis. We observed that the increase in HDL cholesterol was due to a 29% increase in HDL2 cholesterol. Increased HDL2 cholesterol was reported previously by our group after daily consumption of fish or fish oils by subjects with type 2 diabetes or at risk of heart disease (23, 37). In contrast, Grimsgaard et al (19) surmised that both EPA and DHA increase HDL2 cholesterol because both fatty acids increased the ratio of HDL cholesterol to apo A-I. DHA increased HDL cholesterol and EPA decreased apo-AI, suggesting an increased surface-to-core ratio of the HDL particle and a redistribution of the HDL subclasses toward the larger HDL2 particles (41). The mechanisms by which DHA increases HDL cholesterol are not known, but may be related to alterations in lipid transfer protein activity, which decreases after n-3 fatty acid supplementation (41). In epidemiologic terms, the increase in HDL2 cholesterol could have a marked effect on the incidence of cardiovascular disease, given that HDL2 cholesterol may be the subfraction of HDL cholesterol that may be most protective against coronary heart disease (42).
EPA lowered HDL3, while DHA raised HDL2. Some color on that:
In Cox multivariate survival models adjusted for age and examination year, serum HDL cholesterol of less than 1.09 mmol/l (42 mg/dl) was associated with a 3.3-fold risk of acute myocardial infarction (95% confidence intervals [CI], 1.7-6.4), serum HDL2, cholesterol of less than 0.65 mmol/l (25 mg/dl) was associated with a 4.0-fold risk of acute myocardial infarction (95% CI, 1.9-8.3), and serum HDL3 cholesterol of less than 0.40 mmol/l (15 mg/dl) was associated with a 2.0-fold (95% CI, 1.1-4.0) risk of acute myocardial infarction.
and
OBJECTIVE:
To evaluate which HDL subfraction, HDL2 or HDL3 exerts the greater preventive effect on the Cu(2+)-induced LDL oxidation.
METHODS:
LDL was incubated for 6 h with 2.5 microM Cu2+ in phosphate-buffered saline alone, or in the presence of HDL2 or HDL3 at various protein concentrations. Each sample was subjected to agarose gel electrophoresis, and the amount of lipid hydroperoxide in each sample of LDL was measured.
RESULTS:
There was no significant difference in the levels of LPO between the LDL and LDL + HDL2 cases, whereas a significant reduction was apparent with LDL + HDL3. Both HDL2 and HDL3 significantly inhibited oxidative modification of LDL, as assessed by electrophoretic mobility, in a concentration dependent manner, but this effect was much more pronounced with HDL3.
EPA-alone causes a very significant reduction in HDL3, which is no bueno. And Vascepa 4g/d significantly reduced HDL-C. Such a reduction has been correlated with a large increase in MACE risk:
A decrease in HDL-C of >0.1 mmol/L was associated with a 56 % increase in major adverse cardiovascular events compared with unchanged HDL-C levels. The results were consistent across subgroups based on age, gender, presence of diabetes, primary and secondary prevention.
I noted AMRN researcher's shady reporting of this phenomenon, even misleading a frequent poster here into thinking it wasn't significant, when it was a VERY sig finding.
Once again, throwing away every other nutrient and enzyme that naturally co-exists along with EPA, just because of marketing (really) and LDL-C worries is probably a bad idea. How many centuries of Japanese have been eating fish rich in DHA, DPA and other fatty acids, as well as abundant other nutrients? It doesn't seem to have hurt them much. And keep in mind you absorb multiple times the DHA from natural fish sources than from omega-3 supplements.
If you want the benefits from fish, just eat the fish. Or better yet, just don't eat the bacon double cheeseburger with fries.
But, it doesn't end there. EPA at 4g/d also raises fasting plasma glucose significantly, while lesser doses do not, and DHA does not (at high or low doses)--though taking both or either at higher doses is probably ill-advised for T2D:
This study addressed whether purified EPA and DHA have different effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. We found that DHA, but not EPA, improved serum lipid status, in particular a small increase in HDL cholesterol and a significant increase in the HDL2-cholesterol subfraction, without adverse effects on fasting glucose concentrations. Neither EPA nor DHA affected total cholesterol and both fatty acids reduced triacylglycerols and increased fasting insulin concentrations to a similar extent. DHA supplementation significantly increased LDL cholesterol; however, this was associated with an increase in LDL particle size, which may represent a shift to a less atherogenic LDL particle.
The benefits of n-3 fatty acids have to be weighed against the potential for impaired glucose tolerance, particularly in patients with type 2 diabetes (20–22), although no adverse effect has been seen in healthy volunteers or in hypertensive (25) or dyslipidemic patients (24). We showed in patients with type 2 diabetes that, under carefully controlled dietary conditions, n-3 fatty acids can lead to a deterioration in glycemic control (23). This effect, however, was prevented by a moderate exercise program.
Both EPA and DHA supplementation increased fasting insulin, but only EPA increased fasting glucose. These results are consistent with a differential effect of EPA and DHA on glucose responses in humans. In contrast, lower doses of EPA (900 and 1800 mg/d) did not change fasting plasma glucose or glycated hemoglobin concentrations in patients with type 2 diabetes (53, 54).
Mechanisms underlying the putative adverse effects of n-3 fatty acids on glycemic control include an increase in hepatic glucose output, which may be related to an elevated flux of gluconeogenic precursors to the liver, increased plasma glucagon concentrations, changes in hepatic insulin or glucagon sensitivity, or decreased insulin secretion rates (20–22). The mechanisms responsible for the increase in fasting glucose after EPA but not after DHA supplementation are not known, but may be because EPA increases hepatic glucose production or decreases hepatic insulin secretion more than does DHA.
LDL particle size even sometimes decreases with EPA-only dosing, which is clearly atherogenic:
Nonsmoking treated hypertensive diabetic men and postmenopausal women, aged 40–75 years, were stratified by sex, age, and BMI and randomized to receive 4 g/day purified EPA, DHA, or olive oil (placebo) for 6 weeks in a double-blinded trial. LDL particle diameter was determined by gradient gel electrophoresis (2).
At baseline there were no significant differences among the olive oil, EPA, and DHA groups in plasma LDL cholesterol level and LDL particle size (25.69 ± 0.13 nm, 26.0 ± 0.16 nm, and 25.74 ± 0.16 nm, respectively). Relative to placebo, LDL particle size was decreased by 0.12 ± 0.10 nm (P = 0.49) with EPA and increased by 0.26 ± 0.10 nm (P = 0.02) with DHA after adjusting for multiple comparisons.
These data support our previous study in overweight hypercholesterolemic subjects, in whom LDL particle size increased after supplementation with DHA but not EPA (2).
DHA is beneficial for one's health, and should not be omitted from fish oil just because of LDL-C worries. It is the fatty acid responsible for lowering blood pressure (BP) and resting heart rate (HR), interfering with oxLDL uptake by macrophages, interfering with LDL synthesis, increasing LDL particle size and decreasing LDL-P concentration, increasing HDL-C and especially HDL2, and is much better than EPA at lowering VLDL-C. It also has no effect on fasting glucose levels.
EPA taken alone on the other hand has no effect on BP or HR, has modest lowering effects on LDL-C at doses of 4g/d (although the above study showed it increased LDL-C slightly at the same dose), may decrease LDL particle size (atherogenic), increases oxLDL uptake by macrophages, decreases HDL-C and especially HDL3, and increases fasting glucose levels in T2Ds.
So I do not think it wise to take 4g/d EPA only. Or any dose of EPA only. Risk reduction is apparent when peoples cut back on atherogenic foods and replace them with cardio-protective foods (this is even true of LA containing foods). Replacing mammalian meats and dairy with non-fried fish is clearly cardio-protective, and of course lots of DHA and DPA etc are naturally present in the fish along with EPA.
This over-focus on LDL-c imo misses the forest for the trees.
Lastly, even with DHA, it appears that isolated fish oils at higher doses (4g/d+) have mixed benefit. Although lipid profiles improve, there are a number of atherogenic markers that increase, including TBARS and decreased serum vit E.
One placebo-controlled study of around 300 subjects that tried a dose of 4g/d n-3 failed, and actually showed a trend towards increased MACE risk in fish oil group:
The authors (experienced cardiologists) hypothesized that, among other possibilities for the failure, optimal dose statins and low dose aspirin may "mask the potential of n-3 to show benefit." And so what is left is the potential harm, which they also hypoethsized may result due to increased lipid peroxidation at high dosages.
Net net, I think REDUCE-IT will overwhelmingly fail (and I haven't even touched on dropouts going on fenofibrate or OTC n-3 while remaining ODIS). But I hope I'm wrong. It would be a nice consolation for losing money on my future short positions if that happens.
Planning to short AMRN before 2nd IA rec announcement and will re-short with profits plus additional principal just before final data. In this manner I can potentially turn a 60% - 80% short profit into a compounded 120%+ profit.
Cheers and GL
"Think for yourselves and let others enjoy the privilege to do so, too."
