Lp(a) in Youth Tracks With Adult ASCVD Risk in Cohort Studies

December 07, 2022

High levels of lipoprotein a, or Lp(a), in youth predict an elevated risk from atherosclerotic cardiovascular disease (ASCVD) in middle-aged adulthood, but apparently not by directly affecting vascular disease progression, suggest both separate and pooled analyses of two longitudinal cohort studies.

The risk for ASCVD events in late adulthood was at least doubled for young participants with elevated Lp(a), measured from about age 10 to late teens or early 20s, in the Cardiovascular Risk in Young Finns Study (YFS) and the Louisiana-based Bogalusa Heart Study (BHS).

But in neither study was Lp(a) in youth associated with increased carotid artery intima-media thickness (IMT) in adulthood.

Given that carotid IMT tracks with LDL-cholesterol, body-mass index (BMI), and other standard predictors of ASCVD risk, the current analyses "may suggest that elevated Lp(a) levels do not confer cardiovascular risk by contributing to early preclinical vasculopathy," write Olli Raitakari, MD, PhD, Turku University Central Hospital, Finland, and colleagues in a report published November 28 in Circulation.

Still, elevated Lp(a) at a young age is a predictor of substantially increased risk for "early-onset" ASCVD events in adulthood, Raitakari told theheart.org | Medscape Cardiology.

"Based on all available evidence, including our study, it could be argued that Lp(a) should be measured as part of the pediatric assessment of serum lipids," he said.

Practice Implications

Elevated Lp(a) is genetically determined and won't directly respond to lifestyle or dietary interventions, Raitakari observed. But it can signal a need for increased attention to ASCVD risk factors that can be modified. "It's important to emphasize early and lifelong adoption of a heart-healthy lifestyle by the child and family members," Raitakari said.

Elevated Lp(a) is a well recognized ASCVD risk factor, observed Amit V. Khera, MD, MSc, "and this study adds that it's a risk factor even in kids or young adults. In that way, it's an important contribution," he told theheart.org | Medscape Cardiology. He was not involved with the current study.

The findings underscore the value not only of measuring Lp(a) but "doing it in young adulthood rather than waiting until middle age," said Khera, vice president of genomic medicine at Verve Therapeutics and a cardiologist at the Brigham and Women's Hospital, Boston.

"It's a relatively common clinical question. For example, if an 18-year-old is referred to me at preventive cardiology clinic with a very high Lp(a), we haven't really had a lot of data to say what that means about their risk over the next three decades," he said. "So, this paper does meaningfully fill that gap in our understanding."

Doubling of Risk

In the YFS analysis, 95 of the 3596 (2.7%) participants who entered the study as children were diagnosed with ASCVD at a median age of 47 (range, 31-56), the report notes. The Lp(a) levels in the cohort had been measured at participant ages of 9-24 years.

The hazard ratio (HR) for an adult ASCVD diagnosis for participants who in youth had elevated Lp(a), defined as 30 mg/dL or higher, was 2.0 (95% CI, 1.4 - 2.6) compared with those without elevated Lp(a), the group reported. The HRs for coronary heart disease and for noncoronary atherosclerotic events were both similarly increased.

Smoking, high BMI and LDL cholesterol were also independently associated with increased ASCVD risk, the report states.

Results were similar in a comparable analysis of 587 White BHS participants with data on both Lp(a) in youth and events in adulthood. Those with elevated Lp(a) had an HR of 2.5 (95% CI, 0.9 - 6.8) for adult ASCVD after adjustment for age and sex; it was similar at 2.4 (95% CI, 0.8 - 7.3) on further adjustment for LDL cholesterol and BMI.

The corresponding HR in multivariate pooled analysis of the two cohorts was 2.0 (95% CI, 1.0 - 3.7, P = .04). The adjusted HR per standard deviation increment in youth LDL cholesterol was 1.34 (95% CI, 1.0 - 1.8, P = .05).

"We are on the cusp of knowing — not necessarily in kids but for adults who already have heart disease — whether or not reducing Lp(a) is helpful in preventing heart attacks or strokes," Khera said. 

He pointed to several randomized trials that are exploring or will soon test whether pharmacologic therapy targeting Lp(a) for secondary prevention can improve clinical outcomes.

They include the HORIZON trial that has randomly assigned more than 8300 secondary-prevention patients to receive the Novartis antisense agent pelacarsen (TQJ230) or placebo. And, as recently announced, a phase 3 trial of Amgen's Lp(a)-lowering small interfering RNA (siRNA) agent olpasiran (AMG 890) is in the works.

"Within the next 5 years," Khera said, "we're going to know whether elevated Lp(a) is a modifiable risk factor, and that is scientifically exciting and clinically quite important."

Raitakari and co-authors report no relevant financial relationships. Khera is an employee of Verve Therapeutics and has served as a scientific advisor for Novartis, Amgen, and Silence Therapeutics.

Circulation. Published online November 28, 2022. Full Text

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