This article was written in collaboration with Dr. Leslie Cho, MD.
Director of the Cleveland Clinic’s Women’s Cardiovascular Center.
Lp (a) OR LIPOPROTEIN (a), A BIOMARKER FOR HEART DISEASE AND STROKE
Cardiovascular disease remains the leading cause of death and disability worldwide.
Despite advances in lipid management, there remain significant risks of heart disease and stroke in patients treated with current therapies such as statin. In the Fourier analysis of over 27,500 patients with the cardiovascular disease treated with a statin and with an average LDL of 92 mg/dL, the composite of cardiovascular death, MI or CVA occurred in 7.4% over a period of 2 years. This was 20% higher than if evolocumab, a PCSK9 inhibitor, was added to the statin (5.9%). For this reason, there is a need to investigate other contributors as possible therapeutic targets. Lipoprotein (a) or Lp (a), is a promising biomarker that could be used to refine ASCVD risk assessment in patients who have never had heart disease and potentially prevent further heart attacks or stroke in populations at risk who have already suffered from atherosclerotic heart disease. Lp (a) is estimated to be elevated in approximately 20% of the world population.
What is Lipoprotein (a) or Lp (a)?
Lp (a) is a protein that transports cholesterol in the blood. Lp (a) is a lot like LDL or bad cholesterol, except that it is a lot stickier to the blood vessels. Basically, it is an LDL particle with an added protein, the apo (a), which is assembled in the liver. An individual Lp (a) level is 90% genetically determined as an autosomal codominant inheritance pattern. The level of Lp(a) is not affected by diet or a healthy lifestyle.
What is the connection between Lp (a) and heart disease and stroke?
Lp (a) induces atherosclerosis by carrying the bad cholesterol LDL and attaching it to the oxidized phospholipids and the macrophages in the vessel walls. It forms foam cells, fatty streaks, and eventually plaque build-up that will narrow the inside of the arteries and produce a lack of oxygen to the cardiac muscle. Not only that, Lp (a) tends to reduce the body’s ability to dissolve clots by interfering with the action of plasminogen. So, high levels of Lp (a) favor an environment of plaque build-up and clot formation, the two ingredients for heart attack and stroke.
How do we measure Lp (a)? Which patients should have an Lp (a) measured?
Guidelines recommend reporting Lp (a) levels as “nmol/L” using an assay calibrated against the WHO, the International Federation of clinical chemistry, and lab medicine. Some labs reported Lp (a) values in mg/dL. The 2018 ACC/AHA cholesterol guidelines suggest individuals with Lp (a) levels > 125 nmol/L (or >50 mg/dL) are at higher risk.
Testing for elevated Lp (a) rarely occurs in routine clinical practice. At least once in a person’s lifetime, screening for elevated Lp (a) is reasonable in patients with a personal history or a first-degree relative with premature ASCVD such as MI, CVA, or coronary intervention occurring at an early age (<55 yo for men and <65 yo for women). It is also reasonable to screen patients with severe hyperlipidemia (LDL >190 mg/dL) such as seen in familial hypercholesterolemia.
How do we treat an elevated Lp (a)?
Commonly used preventive strategies of diet and a healthy lifestyle are not effective. Statin drug therapy does not affect Lp (a) levels and patients with coronary artery disease and elevated Lp (a) levels have more recurrent heart disease and stroke despite statin treatment.
Niacin reduces Lp (a) levels by 20-30% but there was no improvement in outcomes in AIM-HIGH or HPS2 THRIVE studies.
Hormone replacement therapy can reduce the Lp (a) levels with an increased risk of an adverse event.
Apheresis is a dialysis-like treatment, and can transiently lower Lp (a) levels by 75% in most refractory patients. However, it is costly and cumbersome.
Currently available data from the PCSK9 showed that in the Fourier study, evolocumab reduced Lp (a) by 27% and reduced a composite of MI, CVA, cardiac death, and revascularization by 10% in a subgroup of patients with the highest level of Lp (a). Similar results were obtained with Alirocumab in the Odyssey clinical trial.
Novel therapies are being developed to reduce the levels of Lp (a). A new antisense medicine, Pelacarsen, is designed to reduce the formation of Lp (a) in the liver and reduce the circulation levels by 80%. In a phase 2 study of Pelacarsen, 80 mg was administered monthly by sc injection, and Lp (a) levels were reduced to <125 nmol/L or <50 mg/dL in 98% of study subjects. Lp (a) HORIZON is a global, placebo-controlled, double-blind study that just completed enrollment of 8,325 patients with ASCVD and elevated Lp (a) (>175 nmol/L or >70 mg/dL). Results are expected in 2025.
OCEAN (a)-DOSE evaluated Olpasiran, a small interfering RNA designed to lower the body’s production of Lp (a) in 281 patients with Lp (a) >150 nmol/L and ASCVD. Olpasiran administered at a dose of 225 mg sc every 12 weeks to patients with a mean baseline of 260 nmol/L reduced Lp (a) to >90% from baseline at up to 48 weeks.
OCEAN (a) will enroll 6,000 patients with ASCVD and Lp (a) > 200 nmol/L (or >90 mg/dL) to Olpasiran or placebo given every 12 weeks subcutaneously and evaluate the effect on major cardiovascular outcomes. The study should be completed by 2026.
Indian sub continental residents have naturally elevated LPa genetically.
Thank you for your comment. Existing studies identify Black and South Asian patients as populations with elevated Lp(a). The results of these studies are difficult to interpret due to different sample sizes and the assay variability for the Lp(a) measurements.
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