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Vascepa, Broadens Cardiovascular Therapy, It's Not All About LDL-C

|Includes: Amarin Corporation PLC (AMRN)

A lot of focus has been centered on LDL-C (bad cholesterol) as being an important cardiovascular marker and while, yes, it is true, it isn't all encompassing as some might think as can be seen in this video that I posted in a previous blog:

A presentation from the 2007 American Heart Association Scientific Sessions entitled Advances in the Detection of Rupture-Prone Plaque: The Role of Lp-PLA2 in Cardiovascular Risk Assessment.

Key points, as little as 25% of premature Coronary Heart Disease is attributable to elevated LDL-C values.

50% of persons who develop CHD are missed with total cholesterol. As mentioned in a prior blog, this was one of the main factors that prompted the JUPITER trial to take a look at elevated hsCRP levels.

So now let's look at the ANCHOR trial results, published in the American Journal of Cardiology:

Involves: high-risk statin-treated patients with residually high triglyceride (NYSE:TG) levels (=200 and <500 mg/dl) despite low-density lipoprotein (NYSE:LDL) cholesterol control (=40 and <100 mg/dl).

These are patients who have already managed to get their LDL-C levels into a relatively safe target zone, so the goal is to treat these patients to further reduce triglycerides levels as well as reducing these other noted CV markers, e.g. lp-PLA2, hsCRP, apo B, apo CIII, VLDL while maintaining lower levels of LDL-C.

As we saw in the JUPITER study, based on the fact that half of all vascular events occur in patients with normal or low levels of LDL cholesterol, LDL-C wasn't the indicator of potential major adverse cardio events when compared with hsCRP levels. So where some might narrowly focus on LDL-C levels in ANCHOR, that is missing the overall framework when considering cardio-risk markers.


A huge study that was run on a Japanese population that typically has a better diet than the US population, the requirement to participate was having at least 117mg/dL of total cholesterol (TC). LDL-C levels dropped 25% in each arm of the trial yet we saw a 19% relative reduction in major coronary events in the group treated with 1.8 grams EPA and statin over statin alone.

So, what else might be a factor in the reduction of major coronary events? Well, in the JELIS study, the subgroup population who had Trigs >150mg/dL and HDL-C <40 mg/dL saw a 53% reduction in major events:

Subjects with abnormal TG and HDL-C levels (TG =150 mg/dL; HDL-C <40 mg/dL) had an increased CAD hazard ratio (HR, 1.71; 95% confidence interval [CI], 1.11-2.64; P=0.014) vs subjects with normal levels.

As shown in the slide, EPA treatment suppressed the risk for CAD among individuals with abnormal TG and HDL-C levels by 53% (HR, 0.47; 95% CI, 0.23-0.98; P=0.043).

From page 8 of the brief document, "Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids" put forth by the Inflammation Research Foundation:

Dr. Sears, the author, comments on the JELIS findings:

The recent JELIS study has also confirmed the benefits in cardiovascular outcome by lowering the AA/EPA (Arachidonic Acid/EPA) ratio (13). In this study, more than 18,000 Japanese patients were put on statin therapy for four and a half years. Half of these patients received 1.8 grams per day of EPA, and the other half a placebo consisting of olive oil. Those receiving the extra EPA had their AA/EPA ratio reduced by 50%. At the conclusion of the study, those patients supplemented with EPA had had a 20-percent reduction in total cardiovascular events compared to those who were on the placebo. Thus a 20-percent reduction in cardiovascular events correlated with a 50-percent decrease in the AA/EPA ratio, whereas those on the placebo had no reduction in their AA/EPA ratio during the course of the study.

The reason that EPA could have such a profound impact comes from the fact that statins are the only drugs known to increase the production of AA (47). Thus statins can increase silent inflammation. This may be the reason why the combination of statins and high-dose fish oil rich in EPA may represent a preferred method of improving outcomes in cardiovascular patients as demonstrated by the JELIS study (13)

Arachidonic Acid is the precursor, the main driver behind the inflammation pathway, the more AA you have in your system, the more inflammation you'll have. EPA acts as the body's natural counter to execss AA, it competes for the same receptors that are involved in the inflammation pathway, it helps to control excessive inflammatory output. Dr. Sears also points out the importance of Trigs/HDL in determining risk levels:

The connection between the TG/HDL ratio and heart disease was confirmed by studies from Harvard Medical School (43). This research found that the higher your TG/HDL ratio the more likely you would have a heart attack. How much more likely? In that study, those with the highest TG/HDL ratio had 16 times greater risk compared to those with the lowest ratio.

The importance of the TG/HDL ratio can be seen from the recently published results of the on-going Copenhagen Male Study that studied the effect this ratio has on the long-term development of heart disease (20). Researchers tracked healthy patients who had either a low TG/HDL ratio (less than 1.7) or a high TG/HDL ratio (greater than 6). Patients with the low TG/HDL ratio who smoked, didn't exercise, had hypertension and elevated levels of LDL cholesterol, had a much lower risk of developing heart disease than those who had a far better lifestyle and metabolic profile, but a higher TG/HDL ratio. This indicates that lowering the TG/HDL ratio may have a far greater impact on whether the patient develops heart disease than by improving lifestyle factors or reducing hypertension and total LDL levels.

So, broadening the scope, it appears that LDL-C is not the be all end all risk marker that could predict a person's likelihood at having a major adverse cardio event. The good news, Vascepa acts to reduce pretty much every important cardio risk marker (e.g. Trigs/HDL, AA/EPA, hs CRP, lp-PLA2, apo CIII, etc.) whether alone as in MARINE or with a statin as in ANCHOR.

Disclosure: I am long AMRN.