Elevated Lp(a) Can Predict Premature ASCVD Risk

Tong Liu, MD, PhD
Credit: European Society of Cardiology

Results of a new study are adding to the burgeoning evidence base outlining the prognostic value of and the atherogenic risk associated with elevated lipoprotein(a) [Lp(a)].

The study, which was an analysis of 51 studies including more than 100,000 participants, produced results indicating elevated Lp(a) was associated with an increased likelihood of premature atherosclerotic cardiovascular disease (ASCVD), including a more than 2-fold increase in the likelihood of a composite ASCVD outcome as well as coronary artery disease and peripheral artery disease.¹

“The findings of the meta-analysis could be clinically relevant,” wrote investigators.¹ “The patients with higher Lp(a) might suffer from ASCVD earlier, so the Lp(a) testing for reclassification in people who are borderline between moderate and high risk and the preventive measures to lower Lp(a) should be taken in time, especially in males, females, Caucasians, South Asians, [familial hypercholesterolemia] patients, and [type 2 diabetes mellitus] patients.”

If you polled lipidologists and cardiologists, many might that attest there has never been a more exciting time to be involved in the management of dyslipidemia. Buoyed by recent advancements and anchored by decades’ worth of foundational therapy and research, the field has never been more equipped to address . Yet, many of those same opinion leaders and clinicians will admit, the excitement surrounding the potential of an Lp(a)-lowering agent has them waiting with bated breath for future updates in the pharmacologic pipeline.^1,2

However, while the community may be waiting with bated breath on the first agent to receive an indication for reducing Lp(a) the knowledge of elevated Lp(a) can still prove useful in risk stratification. To improve the value of this risk stratification, the current study was launched by Tong Liu, MD, PhD, director of the Department of Cardiology at the Second Hospital of Tianjin Medical University, and colleagues to better inform the prognostic value and effects of elevated Lp(a) among younger populations, which they suggest has been the focus of less research in this arena than their older counterparts.

With this in mind, in¹vestigators designed their research endeavor as a systematic review and meta-analysis of data within the PubMed and Embase databases from inception through November 12, 2023. The primary outcome of interest for the study was the occurrence of any ASCVD at the age <65 years of age, with ASCVD defined as coronary artery disease, peripheral artery disease, or stroke.¹

More than 4900 articles were returned through the investigators' initial search. Of these, 51 studies with a total patient population of 100,540 individuals were included in the systematic review and meta-analysis. Among these 51 studies were 16 cross-sectional studies, 9 prospective cohort studies, and 26 retrospective studies.¹

The mean age of these cohorts ranged from 35.3 to 62.3 years, the proportion of male participants ranged from 0 to 100%, the mean follow-up ranged from 1 to 40 years. Investigators pointed out the definition of elevated Lp(a) varied among studies included, with observed definitions of more than 30 mg/dL, more than 50 mg/dL, top turtles, top quartiles, top quintiles, and so on.¹

A group of 3 studies reported the association and composite ASCVD. Analysis of these studies indicated elevated Lp(a) level was associated with significant higher risks of composite ASCVD events among individuals at an early age (Odds Ratio [OR], 2.15; 95% Confidence Interval [CI], 1.53 to 3.02; P <.001). Further analysis pooling 49 studies focused on individual ASCVD events demonstrated an association between elevated Lp(a) level and overall ASCVD as both a categorical (OR, 2.35; 95% CI, 2.01 to 2.74; P <.001) and continuous variable as per 1 SD increase of the log Lp(a) (OR, 1.36; 95% CI, 1.14 to 1.61; P <.001), but not for other forms of continuous variable.¹

Analysis of data from 3 trials assessing the prognostic value of Lp(a) in patients with familial hypercholesterolemia suggests elevated Lp(a) was associated with premature ASCVD (OR, 3.11; 95% CI, 1.63 to 5.96; P <.001). Analysis of data from 2 trials provided evidence of a significant association between elevated Lp(a) and premature ASCVD events in patients with type 2 diabetes mellitus (OR, 2.23; 95% CI, 1.54 to 3.23; P <.001).

Additional analysis of individual components of ASCVD suggested there was a positive association between elevated Lp(a) levels with risk of premature coronary artery disease (OR, 2.44; 95% CI, 2.06 to 2.90; P <.001) and peripheral artery disease (OR, 2.56; 95% CI, 1.56 to 4.21; P <.001), but not for stroke (OR, 1.25; 95% CI, 0.87 to 1.81; P = .06).¹

Investigators pointed out multiple limitations within their study to consider. These included reliance on articles published on PubMed and Emboss only, measurement of Lp(a) as a continuous and categorical variable limited pooling of all studies, possibility for recall bias associated with retrospective and cross-sectional studies, and assessing for publication bias in meta-analyses by checking for asymmetry in a funnel plot, among others.¹

“Our meta-analysis supports that elevated Lp(a) concentration, which is genetically determined, can predict both composite and individual ASCVD in young patients,” investigators concluded.¹ “The presence of high Lp(a) concentration indicates prospective evaluation and validation as a clinical risk factor in premature ASCVD in Caucasians, South Asians, FH population, and patients with the baseline LDL-c level ≥ 100 mg/dL.”

References:

1. _{^{Tian X, Zhang N, Tse G, Li G, Sun Y, Liu T. Association between lipoprotein(a) and premature atherosclerotic cardiovascular disease: a systematic review and meta-analysis. Eur Heart J Open. 2024;4(3):oeae031. Published 2024 Apr 26. doi:10.1093/ehjopen/oeae031}}
2. _{^{Thau H, Neuber S, Emmert MY, Nazari-Shafti TZ. Targeting Lipoprotein(a): Can RNA Therapeutics Provide the Next Step in the Prevention of Cardiovascular Disease?. Cardiol Ther. 2024;13(1):39-67. doi:10.1007/s40119-024-00353-w}}