Most cases of cardiovascular disease (CVD) – the category that combines heart disease and stroke – are caused by high LDL cholesterol. When LDL rises above about 90 mg/dl, plaque starts to build up on the vessel walls. If changes to diet and exercise don’t reduce LDL enough, statins, ezetimibe, and PCSK9 inhibitors cause huge reductions with minimal side effects. People with genetic mutations that keep their LDL low their whole lives have about a 90% reduction in heart disease risk, so with these drugs we can prevent nearly all cases of heart disease. Even then, though, the risk doesn’t go to zero. There’s another risk factor: Lipoprotein(a), or Lp(a).
Lp(a) is a type of LDL with a disproportionate impact – relative to other forms of LDL – on heart disease. It’s produced in the liver at a level that is genetically determined and stable. The study of people with genetically low LDL found a single patient with the most favorable mutation who got heart disease anyway. His Lp(a) was above the 95th percentile. With a larger sample size, an analysis of the UK Biobank – a study with health histories and blood samples from over 400,000 people – found that about 6% of CVD is caused by high Lp(a).
The American College of Cardiology recommends that people with extremely high LDL or a family history of premature CVD get a blood test for Lp(a). The European Atherosclerotic Society makes a similar recommendation. In both cases, they recommend testing only one time because Lp(a) doesn’t change much over time. The Lp(a) test is cheap, so why not test everyone?
There’s nothing you can do about high Lp(a). Statins interfere with the liver’s production of other forms of LDL, but don’t impact Lp(a). Ezetimibe prevents the small intestine from absorbing dietary cholesterol, so that doesn’t help with Lp(a) either. PCSK9 inhibitors, newer drugs that reduce LDL to astonishingly low levels, do reduce Lp(a) by 27%. But these drugs are expensive, given by injection, and haven’t been studied in people who’s only risk factor is high Lp(a). The cheapest way to get a drug approved to reduce Lp(a) might be to fund a trial for people like that, but as far as I can tell that isn’t happening. People at the 90th percentile of Lp(a) have about eight times the concentration of people at the median of Lp(a), so a 27% reduction may not matter.
There is one drug in late stage trials for treating high Lp(a). A Phase 2 trial found the highest dose reduced Lp(a) by 80%. Building on those early results, the UK Biobank analysis estimated that an 80% reduction in Lp(a) would cause a 23% reduction in CVD risk for people in the highest Lp(a) category. Novartis is now running a Phase 3 trial of the drug, pelacarsen, scheduled to end in 2024. Just like PCSK9 inhibitors, pelacarsen is injected. Another drug, olpasiran, has a similar impact on Lp(a) with much less frequent injection. It just reported results from a Phase 1 trial last week. Presumably either drug would be expensive, but they would be much more effective for treating high Lp(a) than PCSK9 inhibitors. If and when one of these drugs is approved, it would make sense to screen everyone for high Lp(a) once, early in their lives. Patients with healthy Lp(a) would never need to think about it again and patients with high Lp(a) could get treated.