Low Lipoprotein(a) Levels and Cardiovascular Risk
There is no evidence that low levels of Lipoprotein(a) are associated with increased cardiovascular risk. In fact, the relationship is entirely opposite—lower Lp(a) levels are protective, and the concern in clinical practice is exclusively with elevated levels.
The Evidence on Lp(a) and Cardiovascular Risk
High Lp(a) is the Problem, Not Low Lp(a)
High concentrations of Lp(a) are independently associated with increased risk of coronary heart disease and ischemic stroke, while there is no evidence suggesting any cardiovascular risk from low levels 1.
Mendelian randomization and epidemiological studies have consistently demonstrated that elevated Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascular disease, with no suggestion of harm from low levels 2, 3.
Approximately 20-25% of the global population have Lp(a) levels ≥50 mg/dL, which confers increased cardiovascular risk, but no lower threshold has been identified below which risk increases 2, 4.
The Dose-Response Relationship
The relationship between Lp(a) and cardiovascular risk is continuous and progressive—the higher the Lp(a) level, the greater the risk, with no evidence of a J-shaped or U-shaped curve that would suggest harm from low levels 1, 5.
Risk thresholds are defined for elevated levels (>30 mg/dL, >50 mg/dL, >100 mg/dL), but there is no evidence that any value should be considered "too low" 1.
Patients achieving very low Lp(a) levels with emerging therapies (antisense oligonucleotides reducing Lp(a) by up to 90%) have not demonstrated adverse cardiovascular outcomes related to low Lp(a) itself 2, 5.
Clinical Implications
No Physiological Function Requiring Minimum Levels
A physiological function of Lp(a) has not been determined, and there is no evidence that humans require a minimum level of Lp(a) for normal cardiovascular or metabolic function 1.
Unlike HDL cholesterol, where very low levels may indicate other metabolic abnormalities, low Lp(a) levels are simply protective and require no intervention 1.
Therapeutic Goals Support Lower is Better
Current therapeutic development focuses on lowering Lp(a) as much as possible to reduce cardiovascular risk, with antisense oligonucleotides achieving up to 90% reductions without safety concerns related to low Lp(a) levels 4, 5.
The ongoing Lp(a)HORIZON trial is testing whether selective Lp(a) lowering reduces cardiovascular events, based on the premise that lower levels are beneficial 5.
Assessment of new-onset diabetes in patients achieving very low Lp(a) levels will be important in future trials, but this is a precautionary measure for potential off-target effects of therapies, not a concern about low Lp(a) itself 2.
Common Pitfall to Avoid
Do not confuse Lp(a) with HDL cholesterol—while very low HDL cholesterol can be a marker of increased cardiovascular risk, the same does not apply to Lp(a), where lower levels are uniformly protective 1.
There is no justification for screening to identify patients with low Lp(a), as this provides no clinically actionable information 1.