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Wednesday, August 17, 2016 7:38:35 PM
Results: During a mean of 5.1 ± 3.2 years of observation after their second lipid measurements, 2167 (31%) patients had an acute coronary event. Patients having events were significantly older, more often white, male, and smokers and more often had antecedent diabetes, hypertension, coronary heart disease, and myocardial infarctions. Adjusting for covariates, a 10-mg/dL higher initial HDL-C was associated with an 11% (95% CI 7%-14%) lower risk of coronary events. A 10-mg/dL increase in HDL-C between lipid measurements was associated with a 7% (95% CI 3%-10%) lower risk of events. Neither initial or change in triglycerides nor LDL-C predicted subsequent coronary events.
and
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.
Lovaza resulted in an increase in HDL-C by 9.1%, whereas Vascepa resulted in a decrease in HDL-C of 3.5%. (I'm not talking about a tiny study of 8 or *one* patient, but MARINE trial data).
Also there are mixed data out there on LDL-C (for example the one above that showed no positive correlation between LDL and MACE), but most show that lowering VLDL-C is inversely correlated with MACE. Such as:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868060/
Lovaza lowered VLDL-C by 42%, while Vascepa only lowered VLDL-C by 19.5%.
This also showed LDL didn't matter in patients with diabetes, while VLDL (included in non-HDL) very much did:
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).
And I won't restate the beneficial effects of DHA on blood pressure and heart rate, which are strongly correlated with MACE, whereas EPA had no effect on either.
Beyond this, it's not just "LDL," or even "LDL particle size," but also:
Oxidized low-density lipoprotein (oxLDL) and ß2-glycoprotein I (ß2GPI) have been identified in human atherosclerotic lesions and when complexed have been implicated as a pro-atherothrombotic antigen.
Both oxLDL and oxLDL-ß2GPI complex were lower in patients on statins (p <0.001). In statin-naive patients, oxLDL-ß2GPI complex, but not free oxLDL, was associated with severe coronary artery disease (p = 0.036). However, no association was observed in patients on statins. LDL4 and triglycerides increased with oxLDL-ß2GPI complex quartiles (p = 0.001). OxLDL-ß2GPI complex (>0.32 U/ml) was predictive of severe atherosclerosis by receiver-operating characteristic curve analysis in statin-naive patients (area under the curve 0.66, p = 0.002). In conclusion, oxLDL-ß2GPI appears more predictive of coronary artery disease severity than oxLDL alone in statin-naive patients.
Statins aren't bad stuff, if you need them.
But although free oxLDL may be raised slightly by DHA, it doesn't seem to increase oxLDL. In fact:
Enhanced uptake of free fatty acids (FFA) and oxidised low-density lipoproteins (oxLDL) may lead to oxidative stress and microvascular dysfunction interacting with CD36, a PPARa/?-regulated scavenger receptor and long-chain FFA transporter. We investigated CD36 expression and CD36-mediated oxLDL uptake before and after insulin treatment in human dermal microvascular endothelial cells (HMVECs), ± different types of fatty acids (FA), including palmitic, oleic, linoleic, arachidonic, eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids.
A ≥ 24 hour exposure to 50 µM DHA or EPA, but not other FA, blunted both the constitutive (by 23 ± 3% and 29 ± 2%, respectively, p<0.05 for both) and insulin-induced CD36 expressions (by 45 ± 27 % and 12 ± 3 %, respectively, p<0.05 for both), along with insulin-induced uptake of DiI-oxLDL and the downregulation of phosphorylated endothelial nitric oxide synthase (P-eNOS).
At gel shift assays, DHA reverted insulin-induced basal and oxLDL-stimulated transactivation of PPRE and DNA binding of PPARa/? and NF-?B.
In conclusion, omega-3 fatty acids blunt the increased CD36 expression and activity promoted by high concentrations of insulin. Such mechanisms may be the basis for the use of omega-3 fatty acids in diabetic microvasculopathy.
DHA and EPA were about equal in suppression of constitutive CD36 exp, though DHA did a much better job at suppressing insulin-induced CD36 exp and insulin-induced uptake of oxLDL. And even showed capability of reverting negative impacts of oxLDL.
Also DHA (but not EPA) is a potent suppressor of SREBP-1 nuclear abundance by stimulating its proteasomal degradation. This has been implicated in heart and liver diseases, in diabetic and non:
http://www.ncbi.nlm.nih.gov/pubmed/23528177
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759838/
EPA and DHA provide distinct benefits and appear to be synergistic with each other. Perhaps that why people that consume lots of fatty fish all their lives tend to have lower CVD. Not *just* because of EPA.
One more: this study showed EPA and DHA tested alone had about equal effects on lipid profiles (including apoB), but DHA was a little better at raising HDL-C:
http://www.jlr.org/content/44/3/455.full.pdf
And yet, n-3 studies, even high dose, have all recently failed, despite the presence of DHA--which is beneficial (despite what many of you want to believe). Some older studies showed marginal benefit, but the use of statins and daily aspirin was not yet established.
It's probably not enough, though, and Vascepa at 4g probably won't be enough either.
There are cases where adding higher dose n-3s can have dramatic effect, like:
http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.378.9716&rep=rep1&type=pdf
but significantly curbing MACE in patients with CAD who are already on statin + aspirin regimen, especially if they have also made certain dietary and lifestyle changes, after 2 - 6 years of use, is probably too tall an order to fill. Especially when most of the events will come from patients who are farther along, giving Vas less time to work on them. The highest % of events will likely come from patients on study under 1 year, and the second largest from those on study under 2 years.
Jmo
GL
"Think for yourselves and let others enjoy the privilege to do so, too."
-Voltaire
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