Elevated Lipoprotein(a): Background, Current Insights and Future Potential Therapies

Abstract

Lipoprotein(a) forms a subfraction of the lipid profile and is characterized by the addition of apolipprotein(a) (apo(a)) to apoB100 derived particles. Its levels are mostly genetically determined inversely related to the number of protein domain (kringle) repeats in apo(a). In epidemiological studies, it shows consistent association with cardiovascular disease (CVD) and most recently with extent of aortic stenosis. Issues with standardizing the measurement of Lp(a) are being resolved and consensus statements favor its measurement in patients at high risk of, or with family histories of CVD events. Major lipid-lowering therapies such as statin, fibrates, and ezetimibe have little effect on Lp(a) levels. Therapies such as niacin or cholesterol ester transfer protein (CETP) inhibitors lower Lp(a) as well as reducing other lipid-related risk factors but have failed to clearly reduce CVD events. Proprotein convertase subtilisin kexin-9 (PCSK9) inhibitors reduce cholesterol and Lp(a) as well as reducing CVD events. New antisense therapies specifically targeting apo(a) and hence Lp(a) have greater and more specific effects and will help clarify the extent to which intervention in Lp(a) levels will reduce CVD events.

NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient

“…Nicotinic acid can effectively reduce LDL-C by 5-25%, and triglycerides by 20-50% and also raise HDL-C by 15-35% and reduce lipoprotein (a) by 25-40%. [71][72][73] Two large, randomized trials, one with extended-release niacin and one with niacin plus laropiprant, failed to demonstrate benefits on adverse cardiovascular events when added to statin therapy. 74 , 75 Compared to placebo, niacin ± laropiprant use was associated with increased frequencies of adverse effects.…”

Cholesteryl Ester Transfer Protein Inhibition Reduces Major Adverse Cardiovascular Events by Lowering Apolipoprotein B Levels

“…As described previously, CETP inhibition reduces the rate of transfer of cholesteryl ester from HDL into TG-rich lipoproteins, thereby increasing the overall cholesterol content in HDL and the formation of larger HDL particles that are more slowly catabolized, while also depleting the cholesterol content of the apoB lipoproteins, including VLDL, LDL, chylomicrons and their remnants [ 14 ]. CETP inhibitors also improve cholesterol efflux capacity, the first step in reverse cholesterol transport [ 17 , 56 , 60 ], and reduce lipoprotein(a) [ 43 , 56 , 61 ]. During the initial development of CETP inhibitors, their action on HDL-C was the primary focus.…”

Lipoprotein(a): Insights for the Practicing Clinician

“…Niacin is another potential therapy evaluated for the treatment of patients with elevated Lp(a), with studies demonstrating a modest decrease in Lp(a) concentrations [33] but not associated with a reduction in major adverse cardiovascular events (MACEs). A similar effect was demonstrated with cholesterol ester transferase protein (CETP) inhibitors.…”