While we anxiously await the results from the HORIZON trial of Pelacarsen, a medication designed specifically to address the Lp(a) “Felons of the Lipid Neighborhood,” new publications LIKE THIS on the topic of Lp(a) continue to be released.
And an ongoing topic of interest is the effect of statins on Lp(a) levels. Although statins decrease LDL particles, they actually tend to INCREASE Lp(a) levels. Although an unassailable reason for this phenomenon has yet to be established, some have speculated that since statins increase PCSK9 levels and PCSK9 is one of the determinants of Lp(a) production, a statin-induced increase in PCSK9 may be responsible. It’s at least plausible!
So today’s study of interest enrolled 100 patients in Japan who had NOT previously been on statins. And the headline states that, despite Lp(a) levels increasing substantially (>20% from baseline) in 41% of the population, this rise in Lp(a) was NOT ASSOCIATED with subsequent major adverse cardiovascular events (MACE) when these patients were followed over the next 5-6 years.
But let’s look a little deeper at the study results before we make dogmatic assertions. In the 41% of people whose Lp(a) rose significantly from baseline, we see an overall 29% increased risk of MACE. But before the Statin Haters start licking their chops, we also must observe the CONFIDENCE INTERVAL, which ranges from 0.52 to 3.18. In statistical analyses, whenever the confidence interval crosses 1.00, this represents a null result. Basically, if my Lp(a) increases, I can be certain that I’ll have anywhere from a 48% decreased risk of a heart attack after starting a statin OR a 318% INCREASED risk of a cardiac event. Uh…I’m really not confident of anything with this data…we need a much larger sample size.
Additionally, the mean baseline Lp(a) value in the group who experienced a >20% increase was 14.2 mg/dL (for Lp(a) levels, 30-50 mg/dL is “Intermediate” and 50 mg/dL and up is “High”). So even though the average increase was 57.4% in this group, the absolute rise in Lp(a) was around 7 mg/dL. This isn’t much, and generally speaking, THIS WAS NOT A GROUP WITH ELEVATED Lp(a).
So, in my humble opinion, this really doesn’t add much to the discussion. I think articles like THIS ONE showing a 2-4 fold increased recurrent MACE risk in stroke survivors with high Lp(a) levels >70 mg/dL despite statin therapy and THIS META-ANALYSIS showing a 43% increased risk of MACE in statin-treated individuals with Lp(a) >50 mg/dL add much more color to the conversation.
So, in summary, multiple things can be “true” simultaneously:
- Statins, in general, increase Lp(a) levels.
- A statin-induced increase in Lp(a) is not a reason to throw statins in the garbage for a person who could otherwise benefit from the medication.
- People with high Lp(a) levels as a risk-enhancing factor would seem to benefit from consideration of combination therapy to enhance the safety of their Lipid Neighborhood beyond what a statin can confer alone (see the 2026 Cholesterol Guidelines and its nod to the post-hoc analyses of PCSK9i mAb trials).
- We look forward to the clinical trial results of the Lp(a)-lowering therapeutics!
