Lp(a) as ASCVD risk factor
Lipoprotein(a): A risk factor for Atherosclerosis and an emerging therapeutic target.
Key Takeaway
This review article suggests that assessment of Lipoprotein(a) (Lp[a]) might help to identify individuals with increased risk of ASCVD who might benefit from management of other risk factors.
- Understanding of the role of Lp(a) in atherogenesis could help identify targets for treatment aimed at reducing ASCVD risk by lowering Lp(a) levels.
- Lp(a) measurement is suggested to identify individuals with very high levels (>430 nmol/L) of Lp(a), and who have a lifetime ASCVD risk equivalent to that associated with heterozygous familial hypercholesterolemia.
- Patients with high Lp(a) levels should be managed with more intensive approaches to treat other modifiable CV risk factors.
- An effort should be made to increase awareness about the role of Lp(a) as a risk biomarker, and its measurement, and interpretation.
Available lipid-lowering agents have moderate effect on Lp(a) levels and newer potent options being developed might lower residual risk and global ASCVD burden.
Why This Matters
ASCVD remains the main cause of death despite reducing LDL-C with available lipid-lowering treatments.
The ‘residual risk’ might be attributed to different atherogenic factors, such as triglyceride-rich lipoproteins and their remnants, Lp(a), and inflammation.
This review discussed the pathological mechanisms of Lp(a) in ASCVD, evidence supporting its role in ASCVD risk and emerging approaches to reduce Lp(a).
Key Highligts
Lp(a) as a cvd risk factor
Causal and independent relationship between high Lp(a) levels and ASCVD risk in individuals with and without previous ASCVD were supported by various studies*
- In patients with familial hypercholesterolemia, high ASCVD risk is further heightened with elevated Lp(a).
- Mendelian studies suggest an association between high Lp(a) and risk of peripheral artery disease and HF.
- Lp(a) levels were a determinant of residual ASCVD risk in patients treated with high-efficacy statins who achieved very low LDL-C levels for primary prevention.
- Approximately 18 nmol/L increase in Lp(a) was estimated to be associated with a 3.5% increased risk of CHD.
Lp(a) lowering treatments
- Lp(a) has emerged as a potential target with evidence supporting role in ASCVD.
- No drugs are approved to reduce Lp(a) levels.
- Life style has little-to-no impact on Lp(a) levels.
| Drug/drug class |
Effect on Lp(a) |
Additional comments |
|
Statins |
Might increase levels by 8.5%–19.6% |
Inconsistent effects in several studies |
|
Ezetimibe |
No effect |
- |
|
Alirocumab and evolocumab |
Might decrease by |
Smaller percentage reductions in those with higher baseline levels† |
|
Lomitapide |
Lowers levels by 17% |
Reduces hepatic production of lipoproteins by inhibiting microsomal triglyceride transfer protein |
|
Cholesteryl ester transfer protein inhibitors |
Lowers levels by |
Clinical benefit not demonstrated |
|
Estrogen/progestin replacement therapy |
Lowers levels by ≈15% |
Increases atherothrombotic risk and cannot be used |
|
Thyroid hormone analogues |
Found to reduce Lp(a) |
Impact on ASCVD is not known |
|
Aspirin |
Lowers levels by 20% |
Needs confirmation |
|
Inclisiran |
Lowers levels by 19%–22% |
A small interfering RNAs (siRNAs) that acts by inhibiting PCSK9 mRNA translation |
|
Mipomersen |
Mean decrease in Lp(a) by |
Not approved due the adverse effects and no evidence of ASCVD event reduction |
|
Pelacarsen |
Might lower levels from |
Dose-dependent reduction in Lp(a) levels |
|
Lipoprotein apheresis |
Single treatment has been found to lower Lp(a) levels by ~68% |
Resulted in a reduction in mean annual incidence of ASCVD events |
|
Niacin |
Significant decrease in levels by 12% |
Magnitude depends on apo(a)-isoform size and baseline Lp(a) levels |
|
Olpasiran and SLN360 |
Both are siRNAs, and are under development |
Measurement of Lp(a) levels
| Adviced in individuals with |
|
| Suggested in patients on optimal LLT with |
|
| Cascade testing suggested in |
|
*Epidemiological, Mendelian randomization and genome-wide association studies
† Post hoc analysis of the pivotal trials of PCSK9-I demonstrate that relationship between Lp(a) reduction and ASCVD risk reduction was dependent on baseline Lp(a) levels
Abbreviations
ASCVD, atherosclerotic vascular disease; CV, cardiovascular; CHD, coronary heart disease; HF, heart failure; mRNA, Lp(a), Lipoprotein(a); LDL-C, low-density lipoprotein cholesterol; LLT, lipid lowering therapy; mRNA, messenger ribonucleic acid; PCSK9, proprotein convertase subtilisin/kexin type 9; RNA, ribonucleic acid; siRNA, small interfering ribonucleic acid.
Reference
- Di Fusco SA, Arca M, Scicchitano P, Alonzo A, Perone F, Gulizia MM, et al. Lipoprotein(a): A risk factor for atherosclerosis and an emerging therapeutic target. Heart. 2022. doi:10.1136/heartjnl-2021-320708. Online ahead of print. PMID: 35288443.
