Lp(a) and LPA Gene Score 'Modest' Predictors of CVD Risk

Liam Davenport

December 29, 2020

Although lipoprotein(a) (Lpa) levels and LPA genetic risk scores are both significantly associated with atherosclerotic cardiovascular disease (ASCVD) events, they appear to offer only a modest improvement in risk assessment for primary prevention, researchers conclude.

Mark Trinder, MSc, Center for Heart Lung Innovation, the University of British Columbia, Vancouver, Canada, and colleagues studied data on more than 300,000 individuals who did not have ASCVD and who were not taking a cholesterol-lowering drug.

They found that increases in both Lp(a) and a genetic risk score comprising 43 single-nucleotide variants at the LPA gene, which encodes for apolipoprotein(a), were associated with significant increases in a range of ASCVD events, as well as a composite outcome.

However, adjusting the LPA genetic risk score for Lp(a) levels almost completely eliminated the association, and neither measure had a major impact on risk prediction for individuals of borderline to intermediate ASCVD risk.

Trinder said that, taken together, the findings suggest that the LPA genetic risk score provides "comparable risk prediction" for incident ASCVD relative to measured Lp(a).

"The LPA genetic risk score and measured Lp(a) provided modest improvement in risk discrimination beyond guideline-supported risk scores in the context of primary prevention, and this is supportive of Lp(a) being a 'risk enhancing factor,' " he said.

Trinder said that one of the challenges remains the development of efficient strategies to identify individuals with extremely elevated Lp(a) levels and that this requires further research.

However, one expert argues that measuring Lp(a) levels is a useful for all individuals at risk for CVD because the finding helps to better characterize the individual patient and guide management.

The research was presented at the 88th European Atherosclerosis Society (EAS) Virtual Congress 2020 and was published simultaneously in JAMA Cardiology.

In his presentation, Trinder said that Lp(a) is a causal risk factor for ASCVD, but testing for the lipoprotein "in the context of primary prevention for ASCVD remains contentious."

He said that the latest European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines recommend "more liberal testing" of Lp(a), whereas the American College of Cardiology (ACC) and the American Heart Association (AHA) recommend "testing for Lp(a) as a risk-enhancer only."

The implication is that the current findings support the ACC/AHA guidelines over those from the ESC/EAS.

However, Alberico L. Catapano, MD, PhD, professor of pharmacology at the University of Milan, Milan, Italy, and past president of the EAS, did not agree with that interpretation.

He told theheart.org | Medscape Cardiology that the EAS recommends Lp(a) testing for "everybody" at least once in their lifetime because circulating levels are dependent on genetics and are "relatively stable throughout life. We do not have a drug that will work as efficiently as we would like, but still, I think this information is important," Catapano said.

However, the ACC/AHA guidelines discuss Lp(a) in terms of ASCVD risk determination, which "is a completely different issue.

"For instance," Catapano said, "if you take a genetic score such for LPA and you put it in a scoring system" for ASCVD risk, the performance of the receiver operating characteristics (ROC) curve will "increase slightly.

"But that doesn't mean that the classification of the patients will change, because that information is not telling you who is moving from one level to another." It provides the average movement in classification but not information about individuals.

"What is most important to clinicians is the individual patient, because they don't treat the average, they treat the individuals," Catapano said. "That is the information missing there."

To determine the clinical utility of measuring Lp(a) and/or using the LPA genetic risk score in predicting the risk for incident ASCVD, the researchers gathered data from the prospective UK Biobank database of approximately 500,000 volunteers aged 40 to 69 years.

Initially, they focused on 300,839 individuals who did not have prevalent ASCVD and who were not using cholesterol-lowering medication. The mean age of these participants at enrollment was 56.6 years, and 59.0% were women.

The median Lp(a) level was 24.1 nmol/L (interquartile range [IQR], 73.6 nmol/L).

Incident myocardial infarction, coronary artery disease, ischemic stroke, peripheral arterial disease, cardiovascular mortality, and a composite of those outcomes were determined for each individual between the date of enrollment and the end of follow-up on March 31, 2020.

The median length of follow-up was 11.1 years (IQR, 1.4 years).

The researchers found that a 120 nmol/L increase in Lp(a) levels was significantly associated with increased risk for incident composite ASVD events ranging from a hazard ratio (HR) of 1.11 (95% CI, 0.84 – 1.40; P = .44) in individuals of unknown ethnicity to 1.76 (95% CI, 1.27 – 2.25; P = .02) in East Asian individuals.

Because the vast majority of individuals were White/European, the investigators chose to focus on 283,540 White/European persons who did not have prevalent ASCVD and who were not using cholesterol-lowering medication.

Converting the units of the LPA genetic risk score to nmol/L to harmonize with Lp(a) measures, the team found that a 120 nmol/L increase in either Lp(a) or genetic risk score was associated with an increased risk for ASCVD events.

For the LPA genetic risk score, the associations ranged from an HR of 1.09 (95% CI, 1.02 – 1.16; P = .02) for cardiovascular disease (CVD) mortality to an HR of 1.45 (95% CI, 1.41 – 1.50; P = 7.09 × 10-67) for incident coronary artery disease (CAD).

For the composite outcome, the HR per 120 nmol/L increase was 1.26 (95% CI, 1.23 – 1.28; P < .001).

For each increase in Lp(a) level, the associations ranged from 1.09 (95% CI, 1.04 – 1.14; P = .001) for CVD mortality to 1.40 (95% CI, 1.37 – 1.43; P = 1.15 × 10-101) for incident CAD.

For the composite outcome, the HR per 120 nmol/L increase was 1.29 (95% CI, 1.26 – 1.33; P < .001).

The LPA genetic risk score accounted for approximately 60% of the variation in measured Lp(a) levels.

Interestingly, when the researchers adjusted the associations between LPA genetic risk score and the risk for incident ASCVD for measured Lp(a) levels, they found they were substantially attenuated, to the point of becoming nonsignificant or of borderline significance.

Adjusting the associations between Lp(a) and incident ASCVD for LPA genetic risk score had only a minor effect in the majority of cases, however.

The team also examined the impact of Lp(a) and the LPA genetic risk score on risk discrimination for individuals with borderline to intermediate ASCVD risk. The investigators focused on 144,350 participants who had a 10-year ASCVD risk of 5% to 20% on the QRISK3 algorithm.

The area under the ROC curve increased from 0.640 (95% CI, 0.633 – 0.647) to 0.642 (95% CI, 0.635 – 0.649) when adding Lp(a) levels; 0.642 (95% CI, 0.634 – 0.649) when adding the LPA genetic risk score; and 0.642 (95% CI, 0.635 – 0.649) when adding both.

The researchers write that a "major limitation" of the study is its focus on individuals of White/European ethnicity, so the "generalizability of these findings, in particular the LPA genetic risk score, to other ethnic groups requires further research."

Another problem they identify is that the majority of individuals in the study were enrolled "at middle age...and thus the influence of measured lipoprotein(a) and LPA genetic risk score on incident premature and lifelong ASCVD risk remains to be determined in prospective primary prevention cohorts with younger age of enrollment and longer follow-up."

Amgen Inc funded the study, which was also supported by a UK Biobank application. Pradeep Natarajan, MD, is supported by grants from the National Heart, Lung, and Blood Institute and Fondation Leducq and by a Hassenfeld Scholar Award from the Massachusetts General Hospital. Natarajan received grants from Amgen during the conduct of the study and grants from Boston Scientific; grants and personal fees from Apple; personal fees from Novartis and Blackstone Life Sciences; and other support from Vertex outside the submitted work. The other investigators have disclosed no relevant financial relationships.

JAMA Cardiol. Published online October 6, 2020. Full text

88th European Atherosclerosis Society (EAS) Virtual Congress 2020: Abstract Clinical Utility of LPA Genetic Characterization for Primary Prevention of Atherosclerotic Cardiovascular Disease. Presented October 6, 2020.

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