ENDO 2025 was an outstanding meeting with over 7,000 attendees. Topics included reports of preclinical and clinical research, as well as symposia on clinical, basic science, and/or translational research, and “Meet the Professor” sessions on clinical practice. The three Plenary Sessions featured experts in their field, who discussed either Genomics in Health Care, Women’s Reproductive Health: Aging and Environment, and/or Innovative Approaches in Obesity Care.
One clinical session of particular interest addressed Lipoprotein (a) (Lp(a)) and its impact on cardiovascular disease. Lp(a) is a genetically determined lipoprotein. Each particle consists of a low-density lipoprotein (LDL) particle bound to apoprotein (a) (apo(a)). Apo(a) has a structure like plasminogen. Studies have shown that Lp(a) is an independent risk factor for cardiovascular disease (CVD) and is associated with increased risk of atherosclerotic CVD, stroke, calcific aortic stenosis, and thrombosis.
Current guidance recommends measurement of Lp(a) in nmol/L, although Lp(a) is also measured in mg/dL. Levels that confer a high risk of CVD are above 125 nmol/L or 50 mg/dL. About 25% of people living in the U.S. have levels above 50 mg/dL. Levels above 90 mg/dL place people in the 90th percentile for CVD risk. In a global study of 48,135 people with cardiovascular disease, 13.9% had previous measurements of Lp(a). Levels of Lp(a) above 50 mg/dL were seen in 27.9% of those with Lp(a) measurement. Levels of Lp(a) equal to or greater than 150 mmol/L were seen in 26% of patients. Black patients had Lp(a) levels that were about threefold higher compared to white, Hispanic, and Asian patients, and women had higher levels of Lp(a) compared to men. Lp(a) is increased during pregnancy and after menopause and in various disorders such as hypothyroidism and chronic renal disease. Several guidelines recommend universal screening for Lp(a) in adults.
It is not known whether reducing Lp(a) will reduce CVD risk. Several medications that specifically target Lp(a) are in development: an antisense oligonucleotide, several small interfering RNA molecules (including olpasiran, lepodisiran, and zerlasiran), and a small oral molecule (muvalaplin). These investigational medications reduce Lp(a) levels by 80%-99 %. To gain FDA approval, a reduction in CVD events must be demonstrated in a randomized controlled CVD outcomes trial. Pelacarsen, olpasiran, and lepodisiran have such trials ongoing. Results of the HORIZON trial of pelacarsen are anticipated in early 2026.
Medications that lower LDL-C may have a minor effect on Lp(a). Statins can increase Lp(a) by 5-10% and evolocumab and alirocumab (monoclonal antibodies to PCSK9) can reduce Lp(a) by 20-30%. Despite the possibility of increasing Lp(a), statins should be prescribed for adults with high levels of Lp(a) because statins have been proven to reduce ASCVD in multiple randomized controlled trials. Lipoprotein apheresis also reduces Lp(a).
In the absence of an approved medication, the approach to management of patients with high Lp(a) should be control of other risk factors for CVD. For example, LDL-C should be reduced to below 70 mg/dL with a statin, and if necessary, ezetimibe and an inhibitor of PCSK9.
In summary, Lp(a) is an independent genetically determined risk factor for CVD, stroke, calcific aortic stenosis, and thrombosis. Lp(a) screening is recommended for all adults in order to determine whether Lp(a) in individual patients contributes to CVD risk. Until we have an approved medication for reducing Lp(a), the control of other risk factors for CVD is the best practice for the management of patients with elevated Lp(a).
Dr. Newman has no conflicts of interest to report.
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