Elevated lipoprotein(a) [Lp(a)] is independently associated with long-term major adverse cardiac events (MACE), regardless of the baseline atherosclerotic cardiovascular disease (ASCVD), a new study shows. This finding was reported by Adam N. Berman, MD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues in a manuscript published Monday online and in the March 5 issue of the Journal of the American College of Cardiology. It has been proven that Lp(a) is associated with an increased risk of ASCVD. Lp(a) levels above 50 mg/dL (>125 nmol/L), which mark the 80th percentile in population-based studies, are used in U.S. guidelines to identify higher-risk individuals. Traditionally, Lp(a) has been viewed as an unmodifiable risk factor, but advances in genetic medicine could potentially change this understanding and lead to increased screening efforts. The authors conducted a retrospective study that analyzed patients with measured Lp(a) at two large medical centers in Boston (Brigham and Women’s Hospital and Massachusetts General Hospital) between 2000 and 2019. This study included all individuals who are 18 years or older with at least one Lp(a) measurement. Individuals were excluded if they had stage 5 chronic kidney disease, a kidney transplant, were on dialysis, had a malignant neoplasm, or died during the assessment window. The purpose of this study was to investigate the relationship between Lp(a) and MACE among patients with and without existing ASCVD. The primary outcome was a composite of MACE, defined as nonfatal myocardial infarction (MI), ischemic, stroke, coronary revascularization or cardiovascular mortality. Patients were divided into groups based on Lp(a) percentiles: 1st to 50th (0-41 nmol/L), 51st to 70th (42-111 nmol/L), 71st to 90th (112-215 nmol/L), and 91st to 100th (≥216 nmol/L). A total of 21,410 patients were included in the study, of whom 10,181 (62%) had a history of ASCVD and 6,238 (38%) did not. The median age of the cohort was 60 (interquartile range [IQR]: 49-72) years, 40.6% were female, and most (82.8%) were white. At baseline, 23.3% had diabetes and 56.2% had hypertension. Patients with ASCVD had significantly higher median Lp(a) levels compared to those without (37.8 nmol/L vs. 31.1 nmol/L; P < 0.001). The study’s median follow-up of the study was 11.9 years (IQR: 6.2-14.4 years). The study revealed the following outcomes among the entire population; 1,067 (6.5%) individuals experienced a nonfatal MI, 1,373 (8.4%) individuals experienced a nonfatal ischemic stroke, 1,362 (8.3%) individuals underwent coronary revascularization, and 2,416 (14.7%) individuals died of cardiovascular causes. Among patients with a history of ASCVD, the incidence of the primary outcome (MACE) increased with increasing Lp(a) levels: 34.8% in the 1st to 50th percentile, 39.1% in the 51st to 70th percentiles, 41.0% in the 71st to 90th percentile, and 41.5% in the 91st to 100th percentile (P < 0.001). After adjustment, individuals in the highest Lp(a) percentile group had a 26% increased risk of MACE compared with the reference group (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 1.12-1.41; P < 0.001). Additionally, there was a significant increase in the risk of MI across the Lp(a) groups, but no significant difference in cardiovascular mortality or ischemic stroke rates over the follow-up period. Among patients without a history of ASCVD, the incidence of the primary outcome (MACE) during the follow-up period also increased with increasing Lp(a) levels: 423 (11.7%) in the 1st to 50th percentile, 144 (12.9%) in the 51st to 70th percentile, 152 (14.3%) in the 71st to 90th percentile, and 94 (21.6%) in the 91st to 100th percentile (P < 0.001). After adjustment, individuals in the highest Lp(a) percentile group had a 1.9-fold increased risk of MACE compared with the reference group (HR: 1.93; 95% CI: 1.54-2.42; P < 0.001). Additionally, there was significantly higher risk of MI, cardiovascular death, and ischemic stroke among individuals in the highest Lp(a) percentile group. In an accompanying editorial, Nathan D. Wong, PhD, MPH, of the University of California, Irvine, highlighted the novel finding of this study: While the risk of future ASCVD events generally rises with higher Lp(a) levels, this risk plateaus above the 70th percentile (111 nmol/L) in patients with existing ASCVD. Berman and colleagues suggested that those with ASCVD are often already treated with other preventive therapies and are already at increased risk, possibly attenuating the impact of higher Lp(a) levels. Wong countered that even individuals with moderate Lp(a) elevations (e.g., 70th to <90th percentile) are also at increased risk, citing the ongoing Lp(a)HORIZON and OCEAN(a) trials as supporting evidence. The commenter also highlighted the strength of the study, which is the use of a real-world registry of patients with Lp(a) measurements collected from routine clinical care. This approach is important because of the infrequency of Lp(a) screening. Wong also believes that this study is important to motivate further researching effective pharmacological treatments for elevated Lp(a) levels. The editorialist emphasized the ongoing challenge of identifying patients at increased risk for ASCVD. “The identification of patients at increased risk for ASCVD, in both primary and secondary prevention, remains an important challenge and priority,” he wrote. “The current report by Berman et al extends our understanding that Lp(a) and ASCVD risk thresholds can differ between individuals with and without prior ASCVD. The failure to screen and identify those with Lp(a)-associated risks represents a missed opportunity to address this risk, not only with our existing repertoire of treatments but hopefully in the future with the development of promising therapies targeting Lp(a),” he concluded. Sources: Berman AN, Biery DW, Besser SA, et al. Lipoprotein(a) and Major Adverse Cardiovascular Events in Patients With or Without Baseline Atherosclerotic Cardiovascular Disease. J Am Coll Cardiol. 2024;83:873–886. Wong ND. Lipoprotein(a): Ready for Prime Time? J Am Coll Cardiol. 2024; 83:887–889. Image Credit: luchschenF – stock.adobe.com