Elevated lipoprotein(a) is a genetically determined, lifelong risk factor for cardiovascular disease, but current treatments have little effect on its levels, and guidelines do not routinely recommend screening in people without known cardiovascular disease. Although higher lipoprotein(a) is associated with greater risk of atherosclerotic disease, aortic stenosis, and cardiovascular death, most of this risk appears to be concentrated in individuals with very high levels rather than those with mild or moderate elevations. Previous evidence showed that only women in the highest lipoprotein(a) quintile had meaningfully increased 30-year cardiovascular risk.
A recent study aimed to clarify the long-term clinical relevance of lipoprotein(a) by examining continuous levels and clinically relevant cutoffs in 27,748 healthy women followed for 30 years in the Women’s Health Study. The investigators hypothesised that only markedly elevated lipoprotein(a) predicts long-term cardiovascular events, whereas modest elevations do not. They also assessed whether a genetic variant in the LPA gene (rs3798220), which raises lipoprotein(a) levels, shows similar associations with cardiovascular risk.
The study followed healthy female participants in the Women’s Health Study from 1993 to 2023, using baseline blood samples to measure lipoprotein(a) and genetic data in women without major chronic disease, with analyses conducted in early 2025.
The study assessed baseline lipoprotein(a) levels (modeled continuously, by clinical cutoffs, and by percentiles) and an LPA genetic variant as exposures, and evaluated their associations with major cardiovascular events, coronary heart disease, ischemic stroke, and cardiovascular death.
Among 27,748 women followed for nearly 28 years, elevated lipoprotein(a) was associated with higher long-term cardiovascular risk, with modest elevations (≥30 mg/dL) predicting more coronary events and very high levels (≥120 mg/dL or top 1%) also predicting stroke and cardiovascular death. Women carrying the LPA rs3798220 risk allele likewise had increased risk of major cardiovascular events.
Over 30 years of follow-up in nearly 28,000 healthy women, higher baseline lipoprotein(a) levels were linked to greater long-term cardiovascular risk, but this risk was concentrated mainly in those with clearly elevated levels. Only values above about 30 mg/dL (top 25%) were associated with increased cardiovascular and coronary heart disease risk, while extremely high levels (top 1%) conferred roughly a 70% higher risk and were the only ones linked to higher rates of stroke and cardiovascular death. A genetic variant that raises lipoprotein(a) showed similar risk patterns, supporting a causal relationship.
Because lipoprotein(a) is largely genetically determined and minimally affected by lifestyle or current therapies, these results likely reflect true lifelong risk. Although most people with modestly elevated levels are not at substantially higher risk, those with very high lipoprotein(a) face risks comparable to familial hypercholesterolaemia. With powerful lipoprotein(a)-lowering drugs now in late-stage trials, the findings support screening healthy individuals to identify the small but important group who may benefit most from targeted prevention and future therapies.
Overall, these findings show that very high lipoprotein(a) levels predicted greater long-term cardiovascular risk in healthy women, supporting consideration of population screening.
Source: JAMA
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