When Genetics Leaves Its Mark: Is There a Role for Lifestyle Medicine in Elevated Lipoprotein(a)?
Key message
KEY MESSAGE Lipoprotein(a) is a simple and readily available cardiovascular risk marker that is still underused in clinical practice. Lipoprotein(a) is predominantly genetically determined and is an independent cardiovascular risk factor. Measuring it can help identify people whose overall risk is higher than suggested by a standard lipid profile and other conventional risk factors. |
Introduction
Cardiovascular risk assessment traditionally considers factors such as elevated LDL cholesterol, arterial hypertension, diabetes, obesity, smoking, insufficient physical activity and an unhealthy diet.
Many of these factors can be modified through lifestyle change and appropriate treatment, reducing the risk of atherosclerosis and cardiovascular events.
However, in some people, total or residual cardiovascular risk cannot be fully explained by conventional risk factors.
Measuring lipoprotein(a), or Lp(a), can improve lifetime risk assessment and help identify people who may benefit from more intensive prevention.
What is lipoprotein(a)?
Lp(a) is a lipoprotein particle similar to LDL.
It contains apolipoprotein B-100, to which a specific apolipoprotein(a) is attached. Apolipoprotein(a), together with oxidised phospholipids carried by Lp(a), contributes to the particle's proatherogenic, pro-inflammatory and pro-calcific properties.
Lp(a) can cross the endothelial barrier and become retained in the arterial wall, where it contributes to lipid accumulation, inflammation and atherosclerotic plaque development.
It is also involved in aortic valve calcification and is therefore associated with an increased risk of calcific aortic stenosis.
More than 90% of the variation in Lp(a) concentration between individuals is genetically determined. Levels are largely established early in life and then remain relatively stable.
For this reason, an Lp(a) result reflects more than current metabolic status. It indicates inherited, long-term exposure to risk, and in most people it is sufficient to measure it once in a lifetime.
Why is Lp(a) important and which diseases is it associated with?
Large studies strongly support a continuous and probably causal association between elevated Lp(a), atherosclerotic cardiovascular disease and calcific aortic stenosis.
Risk rises progressively with increasing Lp(a) and may be elevated even when LDL cholesterol is relatively low.
The incidence of myocardial infarction is 2.5 times higher among people with elevated Lp(a).
DATA / EVIDENCE Values of Lp(a) up to 75 nmol/L, while levels are considered elevated at 125 nmol/L or above. Newer guidance also indicates increased risk from 105 nmol/L. Values between 75 and 125 nmol/L (or 105 nmol/L) are considered a grey zone and still indicate a moderately higher cardiovascular risk. Higher values are associated with greater increases in risk. |
The strongest associations have been found with:
atherosclerotic cardiovascular disease, including coronary disease and myocardial infarction
calcific aortic stenosis
ischaemic stroke
peripheral arterial disease
The strength of association is not the same for all outcomes. It is strongest for myocardial infarction and aortic stenosis, while associations with ischaemic stroke and all-cause mortality are more modest.
Who should have lipoprotein(a) measured?
Elevated Lp(a) is common in the general population.
It is estimated to be elevated in around 20% of people, or approximately one in five.
Because Lp(a) concentration is largely genetically determined and relatively stable throughout life, measurement at least once in adulthood is recommended.
Measurement is particularly relevant in the following situations:
personal or family history of premature atherosclerotic cardiovascular disease, defined here as men under 55 years and women under 65 years
familial hypercholesterolaemia, confirmed or suspected
a first-degree relative with very high Lp(a), where cascade testing of family members may be appropriate
calcific aortic stenosis
borderline or uncertain overall cardiovascular risk, where the Lp(a) result could influence the intensity of preventive measures
What should be done when Lp(a) is elevated?
An elevated Lp(a) result does not mean that a person will inevitably develop cardiovascular disease.
It indicates a greater inherited component of risk and makes careful assessment and management of other risk factors more important.
Specific therapies that substantially lower Lp(a) are still being evaluated in cardiovascular outcome trials. In current clinical practice, overall risk is therefore reduced primarily through optimal management of modifiable risk factors.
This is where lifestyle medicine.
In people with elevated Lp(a) it is particularly important to apply the principles of lifestyle medicine consistently in order to address associated risk factors such as hypertension and obesity and reduce overall cardiovascular risk.
A person with elevated Lp(a) should be assessed by an internist or cardiologist so that their current cardiovascular status can be evaluated in the context of increased risk and an appropriate plan for follow-up, treatment and support with recommended lifestyle measures can be established.
Alongside an individualised approach, general recommendations include monitoring LDL cholesterol, blood pressure, blood glucose and body weight; avoiding smoking; following a Mediterranean dietary pattern; and aiming for at least 150 minutes of moderate-intensity or 75 minutes of vigorous aerobic activity per week. If health status allows, muscle-strengthening exercise is also recommended at least twice weekly.
Conclusion
Genetic risk is not an unchangeable destiny
WHAT DOES THIS MEAN IN PRACTICE?
Elevated Lp(a) is an inherited and independent risk factor, but an individual's actual risk reflects the combination of Lp(a) and all other risk factors. A healthy lifestyle will usually not substantially lower the Lp(a) concentration itself, but it can substantially reduce overall absolute cardiovascular risk.
For this reason, learning that Lp(a) is elevated should not lead to helplessness. It should prompt earlier and more consistent preventive action.
Measuring Lp(a) therefore has clinical value even before a specific Lp(a)-lowering therapy is available. It can improve risk assessment, help identify family members who may also be at increased risk and support timely, individualised prevention.
Do you know your Lp(a) level?
About the author
Ana Knezović, MD, PhD, specialist in internal medicine, works at Croatia Polyclinic in Osijek and is a member of the Croatian Lifestyle Medicine Association.
References
1. Kronenberg F, Mora S, Stroes ESG, Ference BA, Arsenault BJ, Berglund L, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022;43(39):3925-46. doi:10.1093/eurheartj/ehac361.
2. Mach F, Koskinas KC, Roeters van Lennep JE, Tokgözoğlu L, Badimon L, Baigent C, et al. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2025;46(42):4359-78. doi:10.1093/eurheartj/ehaf190.
3. Duarte Lau F, Giugliano RP. Lipoprotein(a) and its significance in cardiovascular disease: a review. JAMA Cardiol. 2022;7(7):760-9. doi:10.1001/jamacardio.2022.0987.
4. Larsson SC, Gill D, Mason AM, Jiang T, Bäck M, Butterworth AS, et al. Lipoprotein(a) in Alzheimer, atherosclerotic, cerebrovascular, thrombotic, and valvular disease: Mendelian randomization investigation. Circulation. 2020;141(22):1826-8. doi:10.1161/CIRCULATIONAHA.120.045826.
5. Madsen CM, Kamstrup PR, Langsted A, Varbo A, Nordestgaard BG. Lipoprotein(a)-lowering by 50 mg/dL (105 nmol/L) may be needed to reduce cardiovascular disease 20% in secondary prevention: a population-based study. Arterioscler Thromb Vasc Biol. 2020;40(1):255-66. doi:10.1161/ATVBAHA.119.312951.
6. Reiner Ž, Miličić D, Rogić D, Manola Š, Ružić A, Canecki-Varžić S, et al. Povećani lipoprotein(a) – neovisni čimbenik kardiovaskularnog rizika – preporuke za određivanje i liječenje. Liječ Vjesn. 2024;146(1-2):49-61. doi:10.26800/LV-146-1-2-7.
7. Kronenberg F, Bedlington N, Ademi Z, Geantă M, Silberzahn T, Rijken M, et al. The Brussels International Declaration on Lipoprotein(a) testing and management. Atherosclerosis. 2025;406:119218. doi:10.1016/j.atherosclerosis.2025.119218.
