Cholesterol
Olivia C. Welter, PharmD
When discussing cholesterol, most clinicians cite HDL and LDL as the primary cholesterol factors influencing atherosclerotic risk. Lipoprotein(a), also known as Lp(a), is another, less commonly discussed piece of the puzzle in determining risk for atherosclerotic CVD (ASCVD).
In a paper published in the October 2023 issue of the American College of Clinical Pharmacy’s journal Pharmacotherapy, Dixon and colleagues examined Lp(a) as an independent risk factor for ASCVD. This is just one of many publications in recent years that attempt to bring more attention to Lp(a) and why clinicians should include it when assessing ASCVD risk.
The paper summarizes current therapies used to treat Lp(a) elevation and investigational drugs currently being developed to target it.
Lp(a) guidelines
Clinical guidelines vary in their acceptable Lp(a) concentration ranges, but the American College of Cardiology and the American Heart Association (ACC/AHA) advise in their guidelines that less than or equal to 50 mg/dL is an accepted target for individual patients. Any level higher than 50 mg/dL is considered a CV risk–enhancing factor in adults 40 to 75 years old, and warrants statin initiation based on the ACC/AHA guidelines. Overall, recent guidelines clearly demonstrate that Lp(a) must be considered an important factor when evaluating a patient for ASCVD risk.
Screening recommendations for Lp(a) are also variable. Guidelines range from some recommending that all individuals have Lp(a) measured at least once in their lifetime to others suggesting only those at increased risk of ASCVD need to be screened for elevated Lp(a).
In 2018, ACC published a multisociety guideline in the Journal of the American College of Cardiology on the management of blood cholesterol, which recommends screening individuals who have a family history of premature ASCVD.
Lipoprotein(a)
Lp(a) is essentially LDL with a glycoprotein apolipoprotein(a) addition. Although researchers have investigated Lp(a) extensively, its physiological function is still unclear.
A 2016 article published in Journal of Lipid Research by Schmidt and colleagues explored the heavy influence genetics, specifically the LPA gene, have on Lp(a), noting that concentrations can be two- to threefold higher in Africans than in Europeans and most Asian populations. Several studies show that quantitative Lp(a) is a highly heritable trait, with studies investigating twins, families, and siblings all demonstrating a heritability connection. Schmidt and colleagues noted that researchers have yet to discover an explanation as to why a high level of Lp(a) concentration variability exists among different populations.
Current therapies
FDA currently has no approved pharmacological treatments specifically for lowering Lp(a)-associated ASCVD risk. Based on the review conducted by Dixon and colleagues, several observations were noted regarding existing off-label therapies.
While statins are a first-line therapy for lowering LDL, similarly structured Lp(a) molecules react differently and Lp(a) concentrations can even increase when a patient is taking a statin. Ultimately, statin therapy likely does not change Lp(a)-associated ASCVD risk.
Ezetimibe was found to only moderately lower Lp(a) concentrations in one study, while no effect was observed in others.
PCSK9 inhibitors have demonstrated risk- and concentration-lowering effects, specifically in patients with Lp(a) levels elevated above baseline. Similarly, small interfering RNA (siRNA) therapies have also been associated with reduced Lp(a) levels.
Niacin can potentially decrease Lp(a) levels, but the risk of adverse effects in addition to its lack of mortality and morbidity benefit for patients at risk of CVD limits its use.
Investigational pipeline
Eight clinical trials in phases 2 and 3 are currently ongoing to investigate new therapies for lowering Lp(a) levels and their effect on CV risk.
Among these, mechanisms focus on siRNA-based approaches that target LPA gene transcription rate and antisense oligonucleotides, which affect gene translation. Only one investigational drug is taken orally, but most studies are exploring S.C. injections for delivering potential Lp(a)-reducing therapies. Some trials may be completed as early as 2024. ■