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Updated: Jun 25, 2025
Differential Effects of Lipid-lowering Drugs in Modulating Morphology of Cholesterol Particles
Published on: November 10, 2017
New insights into the therapeutic options to lower lipoprotein(a)
A Baragetti1, L Da Dalt1, G D Norata1
1Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università Degli Studi di Milano, Milano, Italy.
Insights
Elevated lipoprotein(a) [Lp(a)] is a cardiovascular disease risk. New therapies targeting Lp(a) show promise for reducing cardiovascular events and mortality.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Genetics
Background:
- Elevated lipoprotein(a) [Lp(a)] is a significant risk factor for cardiovascular diseases (CVD), including aortic valve stenosis, myocardial infarction, and stroke.
- Genetic studies indicate that reduced Lp(a) levels confer cardiovascular protection independent of other risk factors.
- Lp(a) is recognized as a compelling pharmacological target for CVD prevention.
Purpose of the Study:
- To review emerging therapeutic strategies for selectively targeting lipoprotein(a) [Lp(a)] to reduce cardiovascular risk.
- To discuss the clinical development of novel Lp(a)-lowering agents.
Main Methods:
- Review of current and investigational therapies targeting Lp(a).
- Focus on antisense oligonucleotides, small interfering RNAs (siRNAs), apolipoprotein(a) [Apo(a)] inhibitors, and CRISPR-Cas9 gene editing.
- Consideration of ongoing cardiovascular outcome trials.
Main Results:
- Standard lipid-lowering therapies have limited impact on Lp(a) levels.
- Antisense oligonucleotides and siRNAs targeting Apo(a) are in advanced clinical development.
- Novel approaches like Apo(a) inhibitors and CRISPR-Cas9 are entering early clinical stages.
Conclusions:
- Positive results from cardiovascular outcome trials demonstrating Lp(a) reduction (e.g., >80% with pelacarsen, olpasiran, lepodisiran) could establish Lp(a) lowering as a new standard of care.
- This would offer an additional therapeutic target for managing patients at elevated cardiovascular risk.
Background:
Elevated levels of lipoprotein(a) [Lp(a)] represent a risk factor for cardiovascular disease including aortic valve stenosis, myocardial infarction and stroke. While the patho-physiological mechanisms linking Lp(a) with atherosclerosis are not fully understood, from genetic studies that lower Lp(a) levels protect from CVD independently of other risk factors including lipids and lipoproteins. Hereby, Lp(a) has been considered an appealing pharmacological target.
Results:
However, approved lipid lowering therapies such as statins, ezetimibe or PCSK9 inhibitors have a neutral to modest effect on Lp(a) levels, thus prompting the development of new strategies selectively targeting Lp(a). These include antisense oligonucleotides and small interfering RNAs (siRNAs) directed towards apolipoprotein(a) [Apo(a)], which are in advanced phase of clinical development. More recently, additional approaches including inhibitors of Apo(a) and gene editing approaches via CRISPR-Cas9 technology entered early clinical development.
Conclusion:
If the results from the cardiovascular outcome trials, designed to demonstrate whether the reduction of Lp(a) of more than 80% as observed with pelacarsen, olpasiran or lepodisiran translates into the decrease of cardiovascular mortality and major adverse cardiovascular events, will be positive, lowering Lp(a) will become a new additional target in the management of patients with elevated cardiovascular risk.
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