What is Lp(a)?
Lipoprotein(a) [Lp(a)] is a circulating lipid particle that is made up of an LDL particle covalently bound to an apolipoprotein(a) [apo(a)] tail. The apo(a) tail consists of proteins called kringles. The Kringle IV type 2 can vary in length and is an important determinant of the Lp(a) particle size. The Lp(a) particle size is inversely proportional to the plasma concentration of Lp(a), meaning that individuals with smaller Lp(a) particles have higher Lp(a) plasma concentrations and vice versa. Both observational and genetic studies have demonstrated that Lp(a) is an independent risk factor for atherosclerosis and aortic valve stenosis. The increased cardiovascular disease risk is pathophysiologically determined by both the cholesterol content of Lp(a) – as Lp(a) is fundamentally an LDL particle – and by the oxidized phospholipids bound to the apo(a) tail that cause activation of immune cells in the vascular wall.
In the general population, Lp(a) concentrations are skewed to the right, meaning a small proportion of individuals have extremely high Lp(a) levels. There is a continuous association between Lp(a) levels and the risk of cardiovascular disease; the higher the Lp(a) levels, the higher the risk of cardiovascular disease. Approximately 20% of individuals in the general population has elevated Lp(a) levels, defined as levels above 105 nmol/L (50 mg/dl), which is associated with an approximately 1.5-fold increased risk for cardiovascular disease. Approximately 1% of the population has extremely high levels of Lp(a) (>380 nmol/L or 180 mg/dl) and a threefold increased risk of cardiovascular disease.
Lp(a) levels are dependent on ethnicity. Compared to White Europeans and Americans, individuals of African descent have higher Lp(a) levels and Asian populations generally have lower Lp(a) levels.
- Lp(a) is a lipid particle made up of an LDL particle with an apo(a) tail attached to it.
- Lp(a) plasma concentrations are largely genetically determined and therefore remain relatively constant throughout life.
- Approximately 20% of all individuals have elevated Lp(a) levels defined as Lp(a) > 105 nmol/L (50 mg/dl).
- Lp(a) is linearly associated with cardiovascular disease and can give a tripling of the risk for cardiovascular disease.
- Lp(a) lowering therapies, currently investigated in phase 3 trials, can give an up to 90% reduction in Lp(a) concentration.
What determines the level of Lp(a)?
Lp(a) levels are more than 90% genetically determined and remain relatively constant throughout life. Age, gender, and lifestyle have little to no effect on Lp(a) levels. On average, individuals of African descent have four times higher Lp(a) levels than individuals of West-European origin, with median Lp(a) levels around 75 nmol/L. The pattern of inheritance of Lp(a) is complex and not fully understood. Some families, however, have a clear pattern of increased Lp(a) and cardiovascular disease.
When should Lp(a) be measured?
In most hospitals and other care practices, Lp(a) is not included in the standard lipid profile measurement and must be specifically requested by the physician. European and Canadian guidelines recommend measuring Lp(a) levels at least once in adult life, as this is important to accurately assess the individuals cardiovascular risk. In patients that have elevated Lp(a) levels, treatment for other cardiovascular risk factors can be intensified. Lifestyle modifications and treatment of elevated LDL cholesterol levels, hypertension and thrombosis risk are even more important in these patients.
Treatment of elevated Lp(a)
At the moment, no specific Lp(a) lowering treatment options are available. Lifestyle advice, such as a healthy diet and to quit smoking, have little to no effect on Lp(a) levels. LDL cholesterol lowering drugs also barely affect Lp(a) levels. Only PCSK9 inhibitors are able to reduce Lp(a) levels by up to 25%. However, for most patients with extremely high Lp(a) levels, this reduction is insufficient. There are currently Lp(a) lowering drugs being investigated in phase 3 studies that show promising results with up to 90% reductions in Lp(a) levels.