Today's podcast on LDL and pcsk9's

Medical Q&A [Moderated]
1

Thanks for this podcast. I was actually just discussing this exact thing with my cardiologist.

They tend to err with caution and if they see LDL drop “very low” they back off the statin or the PCSK9 if they’re stacked. I inquired why and it came down to an abundance of caution just in case, due to what they perceived as a lack of strong evidence for very low levels causing no harm. They said the evidence that does exist seems to point that way, but it’s sparse.

What they see as “very low” is even lower than the standard “sub 30/40” mentioned in the cast. More like 15 it seemed. And it was noted they’ve seen it bottom out at 0 for those stacking.

I’m one of those “special cases” mentioned. My LDL is around 30. At one point as low as 27 on an all vegan diet. But it was frankly too hard to maintain macros and the volume of food I needed as an endurance athlete was nuts. Also had some deficiencies creep in for things like omega-3’s.

It was, I think, around 60 or 70 when I had a cardiac infarction. My Lp(a) is very, very high (ballpark 300). Which the doc said is the main driver of my ASCVD at my “young age”.

PCSK9’s caught my interest as the only known treatment on the market to bring down Lp(a), albeit modestly.

Ok, now. To my question….what interests me in obtaining very low LDL are studies like the GLAGOV study (Nicholls et al, 2016) and the PACMAN-AMI (Raber et all, 2022).

These show actual reductions in atheroma volume after stacking and achieving LDL levels below 25. With some indication that lower is better. The reductions seem to range from -0.95% to -2.13%(!!) after about one year.

These are relative reductions in volume, not absolute, if I interpreted correctly.

Questions:

  • Do we know if this effect continues? Does it plateau?
  • How does this translate to risk reduction for an individual? e.g. say it is linear and a subject experiences a -2% reduction for two years (mine as well be optimistic). This is contrasted with an expected increase without treatment. So what’s a 10 year risk assessment for patient a who’s been on a PCSK9+statin stack and <25 LDL for 10 years vs no medication? Statin only?

One more:

If someone is on a PCSK9 + statin stack and has a very low LDL…how effective is that at countering a few more risky choices like Smoked Brisket and Hamburgers. Can they get through spring weekly BBQ/Grilling without it shooting up? Is the only thing that matters the LDL at the end of the day with regards to high saturated fat intake?

I’m curious what BBM’s take on these are.

2

Jkyle,

Thanks for the post. To your question:

  1. I’m not really aware of evidence adequately addressing this specific outcome further.
  2. I don’t know with respect to atheroma volume change, but we have prediction tools based on other metrics and I think those are fine to use to make decisions about management.
  3. There are different potential harms from those foods outside of LDL-derived changes. I do not think these medications alter those pathways a ton, save for the anti-inflammatory effect of statins, though I’m not sure by how much. I personally wouldn’t sweat it, as evidenced by the fact that I am not a vegetarian at this point.

-Jordan

3

I’m aware of those data on plaque regression after achieving very low levels, with evidence that a ~1% reduction in plaque volume associated with an ~18% reduction in CV events, with most plaque regressions reported in the range of 1-2.5%. There’s also some other evidence suggesting the possibility of plaque regression from other interventions aside from statins/PCSK9i, including SGLT2 inhibitors and angiotensin receptor blockers, as well as aerobic exercise.

To your questions –

1- We don’t know whether the effect continues, as we cannot extend our claims beyond the durations studied.

2- Risk translation as described above, but again can’t speak to ongoing/additional risk reduction over time, although it would be plausible based on our current understanding of how risk accumulates.

3- Agree with Jordan’s take here