High Lipoprotein(a) Levels’ Hit on Heart Health Doesn’t Discriminate

All sex, race, and risk category groups appeared to be affected by the heart disease risk posed by elevated lipoprotein(a), or Lp(a), according to pooled analysis of primary prevention studies.

Compared with people with below the median Lp(a) level of 3.6 mg/dL, those with higher levels tended to have more atherosclerotic cardiovascular disease (ASCVD) events over 2 decades. The risk was significant for those in the 75th to 89th percentile (median 25.9 mg/dL, adjusted HR 1.18, 95% CI 1.09-1.28) and 90th percentile or above (median 52.6 mg/dL, aHR 1.46, 95% CI 1.33-1.59)

Elevated Lp(a) predicted incident ASCVD events to a similar degree across groups — though people with diabetes appeared at outsized risk compared with nondiabetics (P=0.0056 for interaction). People with both diabetes and Lp(a) in or above the 90th percentile had a HR estimate of 1.92 (95% CI 1.50-2.45), according to researchers led by Nathan Wong, PhD, of the University of California Irvine.

“Our study represents the largest and most ethnically diverse U.S. population-based pooled cohort analysis of Lp(a) in relation to ASCVD events in primary prevention groups with significant representation of both female and Black participants,” the authors noted in the Journal of the American College of Cardiology.

“It is hoped these data will be helpful to better inform investigators on the feasibility and design of future clinical trials targeting Lp(a) to reduce ASCVD risk in primary prevention groups, including diverse populations and patients with [diabetes mellitus],” they concluded.

Wong and colleagues analyzed pooled data from five prospective studies: MESA, CARDIA, Jackson Heart Study, Framingham Heart Study-Offspring, and ARIC. Their study is consistent with prior work establishing elevated Lp(a) as an independent risk factor for ASCVD.

Lp(a) is a highly atherogenic particle, though it has usually been considered an unmodifiable cardiovascular risk factor due to circulating levels of Lp(a) being largely genetically determined with little contribution from lifestyle. Lp(a) trends modestly higher in women than in men, particularly after menopause, and substantially higher in Black individuals.

Universal screening for Lp(a) is not endorsed by U.S. guidelines and is infrequently performed. When it is assessed, Lp(a) of 50 mg/dL or greater has been identified as a risk-enhancing factor to initiate or intensify statins or other preventive therapies, according to U.S. guidelines.

Nevertheless, a recent study showed that Lp(a), even at levels well below currently accepted risk thresholds, predicted cardiovascular risk more than a decade later in a real-world cohort of patients with or without baseline ASCVD.

One major question is whether strategies to reduce Lp(a) concentrations actually reduce cardiovascular risk for diverse groups, according to an accompanying editorial by Gregory Schwartz, MD, PhD, of Rocky Mountain Regional VA Medical Center and the University of Colorado School of Medicine in Aurora.

Two phase III trials are underway to test novel Lp(a)-lowering therapies for secondary prevention: Lp(a)HORIZON on pelacarsen injected monthly and OCEAN(a)-Outcomes on olpasiran injected every 12 weeks.

“Although existing ongoing cardiovascular outcomes trials targeting Lp(a) are focused on higher-risk groups with pre-existing ASCVD, information on the value of Lp(a) as a predictor of cardiovascular risk in persons without ASCVD can be of value for informing the development of future clinical trials in such groups,” Wong’s group stressed.

Schwartz also emphasized the “need to ensure adequate representation of diverse populations that might benefit from such treatment.”

For the present analysis, the investigators took five U.S. prospective studies and pooled them for a total study population of 27,756 people without preexisting ASCVD who were age 20-79 years. This cohort included approximately 55% women, 36% Black people, and 7.6% patients with diabetes.

Follow-up reached an average of 21.1 years across cohorts.

Out of the composite ASCVD endpoint components, Lp(a) predicted myocardial infarction, revascularization, stroke, and coronary heart disease death individually, although not total mortality.

Wong and colleagues acknowledged that their study included fairly few Asian participants. Individual cohort studies also measured Lp(a) differently, often using assay methods without standardized calibration.

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