Lipoprotein(a) as a treatable cardiovascular risk factor: measurement, risk thresholds and what the outcome trials mean for practice

Lipoprotein(a) [Lp(a)] is a genetically determined, low-density lipoprotein-like particle that raises the risk of myocardial infarction, large-artery ischaemic stroke and calcific aortic stenosis independently of LDL cholesterol. Roughly one adult in five has a concentration above 125 nmol/L (50 mg/dL), the threshold at which most guidance now labels risk as high. This review synthesises, for the general physician, what is settled and what remains open now that the first outcome trial of targeted Lp(a) lowering has reported. Mendelian randomisation and prospective cohorts, including the UK Biobank, the Copenhagen studies and the 30-year Women's Health Study, establish a continuous, causal and additive relation with cardiovascular events that persists at low achieved LDL cholesterol. Because concentration is stable, a single molar (nmol/L) measurement suffices for most adults, with repeat testing reserved for postmenopausal women and borderline values that would change a decision. Existing management is indirect: intensive LDL-cholesterol lowering, PCSK9 inhibitors (which lower Lp(a) by about a quarter), individualised aspirin decisions and lipoprotein apheresis for progressive disease. Antisense (pelacarsen) and small interfering RNA (olpasiran, lepodisiran, zerlasiran) agents and the oral inhibitor muvalaplin lower Lp(a) by 80% or more in phase 2 trials. However, on 4 September 2026 the first outcome trial, Lp(a)HORIZON (pelacarsen), was announced not to have met its primary endpoint; its full results and the small interfering RNA outcome trials are awaited. We propose explicit thresholds, an absolute-risk framing and a stepwise algorithm that can be applied now and refined as outcome data are published.