Amarin Corp Plc (AMRN)

[Pyrrhonian]

On LDL-C and MACE risk reduction.

Apparently, because now we have ANCHOR and R-IT to confirm, taking mineral oil concurrent with statins probably impedes their efficacy somehow. But if it's "only" some 10% jump in LDL-C, why does that matter? Isn't that only a 4% or so jump in MACE risk?

No, in fact, it's much more than that. Because statins don't *just* lower LDL-C. They have pronounced anti-inflammatory (far more than EPA), plaque stabilizing (fibrous cap thickening) and plaque reduction effects. They also greatly lower the particle concentration of LDL ("LDL-P"), which is a more accurate reflection of risk than LDL-C (the amount of cholesterol in low density lipoprotein particles).

So it's more like a reduction of all the benefits of a statin, not just the LDL-C bit.

Look at these data:

In the Treating to New Targets (TNT) trial, 10 001 patients with CHD were randomized to receive either 10 mg/day atorvastatin or 80 mg/day atorvastatin to ascertain if intensive atorvastatin reduces MACE (defined in this study as death from CHD, nonfatal MI, cardiac arrest, or stroke) versus less intense atorvastatin.11 Atorvastatin 80 mg as compared with 10 mg atorvastatin significantly decreased MACE (8.7% vs 10.9%, absolute risk reduction 2.2%, relative risk [RR] reduction 22%; HR, 0.78; 95% CI, 0.69–0.89; P < 0.001).

When two equal groups of patients take high dose vs low dose, the high dose group shows a 22% RRR in MACE vs the low dose group. But what about all the other parameters, lipid/lipoprotein levels, etc.?

Well it depends. If they all had well controlled LDL-C to begin with (40-100 mg/dL, as per R-IT protocol), you wouldn't notice an extreme jump. But even with the highest vs the lowest dose available with atorvastatin in subjects with baseline LDL-C of 160, the difference between the two was just 25%:

https://www.nejm.org/doi/full/10.1056/NEJMoa050461

This table shows what you can expect to see across statin regimens and baseline values:

https://academic.oup.com/view-large/35897429

Also, statins do much more than reduce risk by 25% or so vs no treatment in secondary prevention subjects. In these it's more on the order of
> 50% RRR"

Furthermore, the ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac Events) and GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation) trials highlight the benefits of atorvastatin in the 'real world' setting in patients with stable CHD. Compared with 'usual' care, atorvastatin reduced the risk of nonfatal MI by 47-59% (p < or = 0.0002).

So low vs high dose creates a much wider gap in RRR than people might expect.

Now here's something, if this theory is true, where would we realize the largest margin of risk reduction? If it's true that mineral oil impedes statin efficacy, wouldn't it affect those on intense regimens the most? Yes of course, and that's exactly what we see here:

https://www.nejm.org/doi/full/10.1056/NEJMoa1812792

Those on high intensity background statin therapy saw the highest jump in RRR at 31%, followed by moderate intensity at 24% RRR, but then low intensity showed no effect at all from taking either V or mineral oil. That says a lot.

Also, as an aside, apparently those that took mineral oil had a significant increase in anemia. That could also lend itself to an increased risk of MACE.

So all told, the jump in LDL-C and apoB of around 10%, jump in hs-CRP of over 30%, etc., could mean most of the 25% RRR was actually an increase in risk in placebo group, not a decrease of risk in Vascepa group. Just as taking St. John's wart with a statin (or even grapefruit juice for that matter) causes interference, it seems likely that mineral oil can cause similar problems.