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 20%–30%	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 25%–40%	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) (up to 43% with eprotirome)	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 26.4%	Not approved due the adverse effects and no evidence of ASCVD event reduction
Pelacarsen	Might lower levels from 66% to 92%	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	First-degree relatives with premature ASCVD Borderline (5%–7.4%) 10-year ASCVD risk Intermediate (7.5%–19.9%) 10-year ASCVD risk Familial hypercholesterolemia
Suggested in patients on optimal LLT with	Lower-than-expected LDL-C reduction Recurrent ASCVD events
Cascade testing suggested in	Relatives of subjects with high Lp(a) First-degree relatives of subjects with familial hypercholesterolemia

^*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

MAT-KW-2200294/v1/Nov 2022