Burden of elevated lipoprotein(a) among patients with atherosclerotic cardiovascular disease: Evidence from a systematic literature review and feasibility assessment of meta-analysis.

BACKGROUND: Elevated lipoprotein(a) [Lp(a)] level is an independent genetic risk factor that increases the risk of atherosclerotic cardiovascular disease (ASCVD) by 2-4 fold. We aimed to report the burden of clinically relevant elevated Lp(a) in secondary prevention ASCVD population as the evaluation of such evidence is lacking. METHODS: A systematic literature review (SLR) was conducted using Embase®, MEDLINE®, and MEDLINE® In-Process databases to identify studies reporting burden of elevated Lp(a) levels from January 1, 2010, to March 28, 2022. Full-text, English-language studies including ≥500 participants with ≥1 Lp(a) assessment were included. RESULTS: Sixty-one studies reported clinical burden of elevated Lp(a). Of these, 25 observational studies and one clinical trial reported clinical burden of clinically relevant elevated Lp(a) levels. Major clinical outcomes included major adverse cardiovascular event (MACE; n = 20), myocardial infarction (MI; n = 11), revascularization (n = 10), stroke (n = 10), cardiovascular (CV) mortality (n = 9), and all-cause mortality (n = 10). Elevated Lp(a) levels significantly increased the risk of MACE (n = 15) and revascularization (n = 8), while they demonstrated a trend for positive association with remaining CV outcomes. Meta-analysis was not feasible for included studies due to heterogeneity in Lp(a) thresholds, outcome definitions, and patient characteristics. Three studies reported humanistic burden. Patients with elevated Lp(a) levels had higher odds of manifesting cognitive impairment (odds ratio [OR] [95% confidence interval; CI]: 1.62 [1.11-2.37]) and disability related to stroke (OR [95% CI]:1.46 [1.23-1.72)]) (n = 2). Elevated Lp(a) levels negatively correlated with health-related quality of life (R = -0.166, p = 0.014) (n = 1). A single study reported no association between elevated Lp(a) levels and economic burden. CONCLUSIONS: This SLR demonstrated a significant association of elevated Lp(a) levels with major CV outcomes and increased humanistic burden in secondary prevention ASCVD population. These results reinforce the need to quantify and manage Lp(a) for CV risk reduction and to perform further studies to characterize the economic burden.

Assessment of cardiovascular disease risk: a 2023 update.

PURPOSE OF REVIEW: The aim of this study was to highlight the current best practice for atherosclerotic cardiovascular disease (CVD) risk evaluation, including selective use of adjunctive tools for risk stratification [e.g. coronary artery calcium (CAC) scoring] and risk enhancement [e.g. lipoprotein(a) [Lp(a)], polygenic risk scoring (PRS)]. RECENT FINDINGS: New studies have evaluated the efficacy of various risk assessment tools. These studies demonstrate the role of Lp(a) as a risk-enhancing factor ready for more widespread use. CAC is the gold standard method of assessing subclinical atherosclerosis, enabling true risk stratification of patients, and informing net benefit assessment for initiating or titrating lipid-lowering therapy (LLT). SUMMARY: Lp(a) concentration and CAC scoring, apart from the traditional risk factors, add the most value to the current CVD risk assessment approaches of all available tools, especially in terms of guiding LLT. In addition to new integrative tools such as the MESA CHD Risk Score and Coronary Age calculator, the future of risk assessment may include PRS and more advanced imaging techniques for atherosclerosis burden. Soon, polygenic risk scoring may be used to identify the age at which to begin CAC scoring, with CAC scores guiding preventive strategies.

Discordance between lipoprotein (a) and LDL-cholesterol levels in cardiovascular risk assessment in apparently healthy subjects.

BACKGROUND AND AIMS: Lipoprotein(a) is a recognized independent cardiovascular risk factor and apolipoprotein B (apoB) level better reflects the risk than LDL-cholesterol. Despite this cardiovascular prediction mostly relies on traditional risk factors. We evaluated the association between Lp(a) and lipid biomarkers of cardiovascular risk in relation to age and sex in apparently healthy individuals. METHODS AND RESULTS: 422 presumably healthy subjects aged 19-84 were included. Lipid profile, Lp(a), apoB and small dense low-density lipoprotein cholesterol (sdLDL-C) were assayed. Subjects were divided at desirable cut-points of apoB and LDL-C. A group with elevated apoB (≥100 mg/dL) at low LDL-C (≤115 mg/dL) was appointed as high-risk and a group with low apoB but elevated LDL-C as low-risk. Significantly elevated triglycerides, TG/HDL-C and sdLDL-C were found in high risk group, but Lp(a) levels were comparable. TG/HDL-C was the best predictor of high risk with a very good diagnostic accuracy (AUC = 0.85), whereas Lp(a) had no discriminatory power. Women aged ≤40 with low LDL-C ≤ 100 mg/dL and elevated Lp(a) ≥ 40 mg/dL had higher levels of apoB and sdLDL-C (p = 0.002; p = 0.07) than those with Lp(a) < 40 mg/dL, which was not observed in men. In young females increase of LDL-C and apoB significantly raised the risk of elevated Lp(a). CONCLUSIONS: Women younger than 40 with low LDL-C may be at increased cardiovascular risk associated with elevated Lp(a) and apolipoprotein B levels. Inclusion of Lp(a) and apoB in the routine lipid testing providing information on an individual level may improve the prediction of cardiovascular risk in primary prevention.

Potential Novel RNA-Targeting Agents for Effective Lipoprotein(a) Lowering: A Systematic Assessment of the Evidence From Completed and Ongoing Developmental Clinical Trials.

ABSTRACT: An increase in blood lipoprotein (a) [Lp(a)] levels, mostly genetically determined, has been identified as an independent risk factor of atherosclerotic cardiovascular disease. No drug has yet been approved that markedly lowers Lp(a) and thereby reduces residual cardiovascular risk. The aim of this article was to critically review the evidence from clinical development studies to date on the efficacy and safety of new RNA-based therapeutics for targeted lowering of Lp(a). PubMed/MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov were searched without any language or date restriction up to November 5, 2022, and a total of 12 publications and 22 trial records were included. Several drugs were found that are currently in various stages of clinical development, such as the antisense oligonucleotide pelacarsen and the small interfering RNA molecule olpasiran and drugs coded as SLN360 and LY3819469. Among them, pelacarsen has progressed the most, currently reaching phase 3. All these drugs have so far shown satisfactory pharmacokinetic properties, consistently high and stable, dose-dependent efficacy in lowering Lp(a) even by more than 90%, with an acceptable safety profile in subjects with highly elevated Lp(a). In addition, reports of early clinical trials with pelacarsen imply a promising suppressive effect on key mechanisms of atherogenesis. Future research should focus on confirming these beneficial clinical effects in patients with lower average Lp(a) levels and clearly demonstrating the association between lowering Lp(a) and reducing adverse cardiovascular outcomes.

Association of the triglycerides and glucose index and the homeostatic model assessment of insulin resistance with lipoprotein(a), apolipoprotein AI, and apolipoprotein B concentrations in children with normal-weight.

The aim of this study was to compare the association of the triglycerides and glucose (TyG) index and homeostatic model assessment of insulin resistance (HOMA-IR) with lipoprotein(a) (lp[a]), apolipoprotein AI (apoAI), and apoliprotein B (apoB) concentrations in children with normal-weight. Children with normal weight aged 6-10 years and Tanner 1 stage were included in a cross-sectional study. Underweight, overweight, obesity, smoking, alcohol intake, pregnancy, acute or chronic illnesses, and any kind of pharmacological treatment were exclusion criteria. According to the lp(a) levels, children were allocated into the groups with elevated concentrations and normal values. A total of 181 children with normal weight and an average age of 8.4 ± 1.4 years were enrolled in the study. The TyG index showed a positive correlation with lp(a) and apoB in the overall population (r = 0.161 and r = 0.351, respectively) and boys (r = 0.320 and r = 0.401, respectively), but only with apoB in the girls (r = 0.294); while the HOMA-IR had a positive correlation with lp(a) levels in the overall population (r = 0.213) and boys (r = 0.328). The linear regression analysis showed that the TyG index is associated with lp(a) and apoB in the overall population (B = 20.72; 95%CI 2.03-39.41 and B = 27.25; 95%CI 16.51-37.98, respectively) and boys (B = 40.19; 95%CI 14.50-65.7 and B = 29.60; 95%CI 15.03-44.17, respectively), but only with apoB in the girls (B = 24.22; 95%CI 7.90-40.53). The HOMA-IR is associated with lp(a) in the overall population (B = 5.37; 95%CI 1.74-9.00) and boys (B = 9.63; 95%CI 3.65-15.61).   Conclusion: The TyG index is associated with both lp(a) and apoB in children with normal-weight. What is Known: • The triglycerides and glucose index has been positively associated with an increased risk of cardiovascular disease in adults. What is New: • The triglycerides and glucose index is strongly associated with lipoprotein(a) and apolipoprotein B in children with normal-weight. • The triglycerides and glucose index may be a useful tool to identify cardiovascular risk in children with normal-weight.

Pathophysiology, emerging techniques for the assessment and novel treatment of aortic stenosis.

Our perspectives on aortic stenosis (AS) are changing. Evolving from the traditional thought of a passive degenerative disease, developing a greater understanding of the condition's mechanistic underpinning has shifted the paradigm to an active disease process. This advancement from the 'wear and tear' model is a result of the growing economic and health burden of AS, particularly within industrialised countries, prompting further research. The pathophysiology of calcific AS (CAS) is complex, yet can be characterised similarly to that of atherosclerosis. Progressive remodelling involves lipid-protein complexes, with lipoprotein(a) being of particular interest for diagnostics and potential future treatment options.There is an unmet clinical need for asymptomatic patient management; no pharmacotherapies are proven to slow progression and intervention timing varies. Novel approaches are developing to address this through: (1) screening with circulating biomarkers; (2) development of drugs to slow disease progression and (3) early valve intervention guided by medical imaging. Existing biomarkers (troponin and brain natriuretic peptide) are non-specific, but cost-effective predictors of ventricular dysfunction. In addition, their integration with cardiovascular MRI can provide accurate risk stratification, aiding aortic valve replacement decision making. Currently, invasive intervention is the only treatment for AS. In comparison, the development of lipoprotein(a) lowering therapies could provide an alternative; slowing progression of CAS, preventing left ventricular dysfunction and reducing reliance on surgical intervention.The landscape of AS management is rapidly evolving. This review outlines current understanding of the pathophysiology of AS, its management and future perspectives for the condition's assessment and treatment.

Trends and consequences of lipoprotein(a) testing: Cross-sectional and longitudinal health insurance claims database analyses.

BACKGROUND AND AIMS: Lipoprotein(a) (Lp(a)) is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Our goal was to characterize patients undergoing Lp(a) testing and to assess the impact of Lp(a) testing on treatment changes and subsequent ASCVD events. METHODS: A cross-sectional and a longitudinal claims data analysis were performed on 4 million patient records in Germany. Patients were followed up for a maximum of 4 years. RESULTS: In 2015 and 2018, 0.25% and 0.34% of patients were tested, respectively. Testing was more frequent in younger women in the overall population, and in men in the ASCVD population. Patients tested for Lp(a) had more comorbidities and higher ASCVD risk compared to matched control patients. ASCVD hospitalizations were more frequent prior to the first Lp(a) test (5.55 vs 1.42 per 100/person-years). The mortality rate of the Lp(a)-tested cohort and the control group was similar. Mortality was lower in patients with prior ASCVD and Lp(a) testing compared to matched controls with prior ASCVD and no Lp(a) test (2.30 vs 3.64 per 100/person-years, p <0.001). Patients with Lp(a) test received more laboratory examinations and cardiovascular medications and had more visits with specialized physicians. CONCLUSIONS: Lp(a) testing is rarely performed even in patients with very high cardiovascular risk. Patients tested for Lp(a) have more comorbidities and a higher ASCVD risk. Lp(a) testing is associated with more intensive preventive treatment and with positive effects on clinical outcomes and survival. The data support the value of Lp(a) measurements to characterize ASCVD risk and to improve ASCVD prevention.

High levels of lipoprotein(a) - assessment and treatment. / Høyt nivå av lipoprotein(a) ­ utredning og behandling.

Approximately 5 % of the population have highly elevated levels of lipoprotein(a) (Lp(a)), which is a genetically determined risk factor for cardiovascular disease. Measuring lipoprotein(a) can improve cardiovascular risk stratification and have consequences for preventive measures. Treatment is targeted at reducing modifiable cardiovascular risk factors, but Lp(a)-lowering drugs are being trialled. This article reviews the management of lipoprotein(a) in clinical practice.

Commutability Assessment of Candidate Reference Materials for Lipoprotein(a) by Comparison of a MS-based Candidate Reference Measurement Procedure with Immunoassays.

BACKGROUND: Elevated concentrations of lipoprotein(a) [Lp(a)] are directly related to an increased risk of cardiovascular diseases, making it a relevant biomarker for clinical risk assessment. However, the lack of global standardization of current Lp(a) measurement procedures (MPs) leads to inconsistent patient care. The International Federation for Clinical Chemistry and Laboratory Medicine working group on quantitating apolipoproteins by mass spectrometry (MS) aims to develop a next-generation SI (International system of units)-traceable reference measurement system consisting of a MS-based, peptide-calibrated reference measurement procedure (RMP) and secondary serum-based reference materials (RMs) certified for their apolipoprotein(a) [apo(a)] content. To reach measurement standardization through this new measurement system, 2 essential requirements need to be fulfilled: a sufficient correlation among the MPs and appropriate commutability of future serum-based RMs. METHODS: The correlation among the candidate RMP (cRMP) and immunoassay-based MPs was assessed by measuring a panel of 39 clinical samples (CS). In addition, the commutability of 14 different candidate RMs was investigated. RESULTS: Results of the immunoassay-based MPs and the cRMPs demonstrated good linear correlations for the CS but some significant sample-specific differences were also observed. The results of the commutability study show that RMs based on unspiked human serum pools can be commutable with CS, whereas human pools spiked with recombinant apo(a) show different behavior compared to CS. CONCLUSIONS: The results of this study show that unspiked human serum pools are the preferred candidate secondary RMs in the future SI-traceable Lp(a) Reference Measurement System.

Preclinical Toxicological Assessment of A Novel siRNA, SLN360, Targeting Elevated Lipoprotein (a) in Cardiovascular Disease.

SLN360 is a liver-targeted N-acetyl galactosamine (GalNAc)-conjugated small interfering RNA (siRNA) with a promising profile for addressing lipoprotein (a)-related cardiovascular risk. Here, we describe the findings from key preclinical safety studies. In vitro, SLN360 specifically reduced LPA expression in primary human hepatocytes with no relevant off-target effects. In rats, 10 mg/kg subcutaneous SLN360 was distributed specifically to the liver and kidney (peak 126 or 246 mg/g tissue at 6 h, respectively), with <1% of peak liver levels observed in all other tested organs. In vitro, no genotoxicity and no effect on human Ether-a-go-go Related Gene currents or proinflammatory cytokine production was observed, whereas in vivo, no SLN360-specific antibodies were detected in rabbit serum. In rat and nonhuman primate 29-day toxicology studies, SLN360 was well tolerated at all doses. In both species, known GalNAc-conjugated siRNA-induced microscopic changes were observed in the kidney and liver, with small increases in alanine aminotransferase and alkaline phosphatase observed in the high dose rats. Findings were in line with previously described siRNA-GalNAc platform-related effects and all observations were reversible and considered nonadverse. In cynomolgus monkeys, liver LPA messenger RNA and serum lipoprotein (a) were significantly reduced at day 30 and after an 8-week recovery period. No dose-related changes in safety assessment endpoints were noted. No SLN360-induced cytokine production, complement activation, or micronucleus formation was observed in vivo. The toxicological profile of SLN360 presented here is restricted to known GalNAc siRNA effects and no other toxicity associated with SLN360 has been noted. The preclinical profile of SLN360 confirmed suitability for entry into clinical studies.

Pre-clinical assessment of SLN360, a novel siRNA targeting LPA, developed to address elevated lipoprotein (a) in cardiovascular disease.

BACKGROUND AND AIMS: The LPA gene encodes apolipoprotein (a), a key component of Lp(a), a potent risk factor for cardiovascular disease with no specific pharmacotherapy. Here we describe the pharmacological data for SLN360, a GalNAc-conjugated siRNA targeting LPA, designed to address this unmet medical need. METHODS: SLN360 was tested in vitro for LPA knockdown in primary hepatocytes. Healthy cynomolgus monkeys received single or multiple subcutaneous doses of the SLN360 sequence ranging from 0.1 to 9.0 mg/kg to determine the pharmacokinetic and pharmacodynamic effects. Liver mRNA and serum biomarker analyses were performed. RESULTS: In vitro, the SLN360 sequence potently reduces LPA mRNA in primary cynomolgus and human hepatocytes, while no effect was observed on the expression of APOB or PLG. In vivo, SLN360 exposure peaks 2 h after subcutaneous injection with near full elimination by 24 h. Specific LPA mRNA reduction (up to 91% 2 weeks after dosing) was observed with only the 3 mg/kg group showing appreciable return to baseline (40%). No consistent dose- or time-dependent effect on the expression of APOB, PLG or a panel of sensitive markers of liver lipid accumulation was observed. Potent (up to 95%) and long lasting (≥9 weeks) serum Lp(a) reduction was observed, peaking in all active groups at day 21. The minimally effective dose was determined to be 0.3 mg/kg with an ED50 of 0.6 mg/kg. CONCLUSIONS: SLN360 induces a sustained reduction in serum Lp(a) levels in cynomolgus monkeys following subcutaneous dosing. SLN360 has potential to address the unmet need of Lp(a) reduction in cardiovascular diseases.

Online Patient Education Materials Related to Lipoprotein(a): Readability Assessment.

BACKGROUND: Lipoprotein(a) (Lp(a)) is a highly proatherogenic lipid fraction that is a clinically significant risk modifier. Patients wanting to learn more about Lp(a) are likely to use online patient educational materials (OPEMs). However, the readability of OPEMs may exceed the health literacy of the public. OBJECTIVE: This study aims to assess the readability of OPEMs related to Lp(a). We hypothesized that the readability of these online materials would exceed the sixth grade level recommended by the American Medical Association. METHODS: Using an online search engine, we queried the top 20 search results from 10 commonly used Lp(a)-related search terms to identify a total of 200 websites. We excluded duplicate websites, advertised results, research journal articles, or non-patient-directed materials, such as those intended only for health professionals or researchers. Grade level readability was calculated using 5 standard readability metrics (automated readability index, SMOG index, Coleman-Liau index, Gunning Fog score, Flesch-Kincaid score) to produce robust point (mean) and interval (CI) estimates of readability. Generalized estimating equations were used to model grade level readability by each search term, with the 5 readability scores nested within each OPEM. RESULTS: A total of 27 unique websites were identified for analysis. The average readability score for the aggregated results was a 12.2 (95% CI 10.9798-13.3978) grade level. OPEMs were grouped into 6 categories by primary source: industry, lay press, research foundation and nonprofit organizations, university or government, clinic, and other. The most readable category was OPEMs published by universities or government agencies (9.0, 95% CI 6.8-11.3). The least readable OPEMs on average were the ones published by the lay press (13.0, 95% CI 11.2-14.8). All categories exceeded the sixth grade reading level recommended by the American Medical Association. CONCLUSIONS: Lack of access to readable OPEMs may disproportionately affect patients with low health literacy. Ensuring that online content is understandable by broad audiences is a necessary component of increasing the impact of novel therapeutics and recommendations regarding Lp(a).

Finding very high lipoprotein(a): the need for routine assessment.

AIMS: To validate the reported increased atherosclerotic cardiovascular disease (ASCVD) risk associated with very high lipoprotein(a) [Lp(a)] and to investigate the impact of routine Lp(a) assessment on risk reclassification. METHODS AND RESULTS: We performed a cross-sectional case-control study in the Amsterdam UMC, a tertiary hospital in The Netherlands. All patients in whom a lipid blood test was ordered between October 2018 and October 2019 were included. Individuals with Lp(a) >99th percentile were age and sex matched to individuals with Lp(a) ≤20th percentile. We computed odds ratios (ORs) for myocardial infarction (MI) and ASCVD using multivariable logistic regression adjusted for age, sex, and systolic blood pressure. Furthermore, we assessed the additive value of Lp(a) to established ASCVD risk algorithms. Lipoprotein(a) levels were determined in 12 437 individuals, out of whom 119 cases [Lp(a) >99th percentile; >387.8 nmol/L] and 119 matched controls [Lp(a) ≤20th percentile; ≤7 nmol/L] were included. Mean age was 58 ± 15 years, 56.7% were female, and 30.7% had a history of ASCVD. Individuals with Lp(a) levels >99th percentile had an OR of 2.64 for ASCVD [95% confidence interval (CI) 1.45-4.89] and 3.39 for MI (95% CI 1.56-7.94). Addition of Lp(a) to ASCVD risk algorithms led to 31% and 63% being reclassified into a higher risk category for Systematic Coronary Risk Evaluation (SCORE) and Second Manifestations of ARTerial disease (SMART), respectively. CONCLUSION: The prevalence of ASCVD is nearly three-fold higher in adults with Lp(a) >99th percentile compared with matched subjects with Lp(a) ≤20th percentile. In individuals with very high Lp(a), addition of Lp(a) resulted in one-third of patients being reclassified in primary prevention, and over half being reclassified in secondary prevention.

Lipoprotein(a): Pathophysiology, measurement, indication and treatment in cardiovascular disease. A consensus statement from the Nouvelle Société Francophone d'Athérosclérose (NSFA).

Lipoprotein(a) is an apolipoprotein B100-containing low-density lipoprotein-like particle that is rich in cholesterol, and is associated with a second major protein, apolipoprotein(a). Apolipoprotein(a) possesses structural similarity to plasminogen but lacks fibrinolytic activity. As a consequence of its composite structure, lipoprotein(a) may: (1) elicit a prothrombotic/antifibrinolytic action favouring clot stability; and (2) enhance atherosclerosis progression via its propensity for retention in the arterial intima, with deposition of its cholesterol load at sites of plaque formation. Equally, lipoprotein(a) may induce inflammation and calcification in the aortic leaflet valve interstitium, leading to calcific aortic valve stenosis. Experimental, epidemiological and genetic evidence support the contention that elevated concentrations of lipoprotein(a) are causally related to atherothrombotic risk and equally to calcific aortic valve stenosis. The plasma concentration of lipoprotein(a) is principally determined by genetic factors, is not influenced by dietary habits, remains essentially constant over the lifetime of a given individual and is the most powerful variable for prediction of lipoprotein(a)-associated cardiovascular risk. However, major interindividual variations (up to 1000-fold) are characteristic of lipoprotein(a) concentrations. In this context, lipoprotein(a) assays, although currently insufficiently standardized, are of considerable interest, not only in stratifying cardiovascular risk, but equally in the clinical follow-up of patients treated with novel lipid-lowering therapies targeted at lipoprotein(a) (e.g. antiapolipoprotein(a) antisense oligonucleotides and small interfering ribonucleic acids) that markedly reduce circulating lipoprotein(a) concentrations. We recommend that lipoprotein(a) be measured once in subjects at high cardiovascular risk with premature coronary heart disease, in familial hypercholesterolaemia, in those with a family history of coronary heart disease and in those with recurrent coronary heart disease despite lipid-lowering treatment. Because of its clinical relevance, the cost of lipoprotein(a) testing should be covered by social security and health authorities.

Longitudinal Assessment of Lipoprotein(a) Levels in Perinatally HIV-Infected Children and Adolescents.

HIV is an independent risk factor of cardiovascular disease (CVD); therefore, perinatally HIV-infected (PHIV) children potentially have a greater CVD risk at older age. Lipoprotein(a) (Lp(a)) is an established risk factor for CVD in the general population. To evaluate a potential increased CVD risk for PHIV children, we determined their lipid profiles including Lp(a). In the first substudy, we assessed the lipid profiles of 36 PHIV children visiting the outpatient clinic in Amsterdam between 2012 and 2020. In the second substudy, we enrolled 21 PHIV adolescents and 23 controls matched for age, sex and ethnic background on two occasions with a mean follow-up time of 4.6 years. We assessed trends of lipid profiles and their determinants, including patient and disease characteristics, using mixed models. In the first substudy, the majority of PHIV children were Black (92%) with a median age of 8.0y (5.7-10.8) at first assessment. Persistent elevated Lp(a) levels were present in 21/36 (58%) children (median: 374 mg/L (209-747); cut off = 300). In the second substudy, the median age of PHIV adolescents was 17.5y (15.5-20.7) and of matched controls 16.4y (15.8-19.5) at the second assessment. We found comparable lipid profiles between groups. In both studies, increases in LDL-cholesterol and total cholesterol were associated with higher Lp(a) levels. A majority of PHIV children and adolescents exhibited elevated Lp(a) levels, probably associated with ethnic background. Nonetheless, these elevated Lp(a) levels may additionally contribute to an increased CVD risk.

Association of sex-specific differences in lipoprotein(a) concentrations with cardiovascular mortality in individuals with type 2 diabetes mellitus.

BACKGROUND: Compared to individuals without type 2 diabetes mellitus, the relative increase in cardiovascular mortality is much higher in women than in men in individuals with type 2 diabetes mellitus. METHODS: We evaluated data from 7443 individuals (3792 women, 50.9%), aged 20 to 81 years, from two independent population-based investigations, SHIP-0 and MONICA/KORA S3. We analyzed the longitudinal sex-specific associations of lipoprotein(a) with cardiovascular mortality in individuals with and without type 2 diabetes mellitus using Cox regression. RESULTS: During a median follow-up of 20.5 years (136,802 person-years), 657 participants (404 men and 253 women) died of cardiovascular causes. Among individuals without type 2 diabetes mellitus, men had a significantly higher risk for cardiovascular mortality compared to women in unadjusted model and after adjustment. On the other hand, in participants with type 2 diabetes mellitus, the risk for cardiovascular mortality was not different between men and women in the unadjusted model and after adjustment for age, body mass index, low-density lipoprotein-cholesterol, fasting status and study sample (SHIP-0, MONICA/KORA S3). Further adjustment for lipoprotein(a) concentrations had no impact on the hazard ratio (HR) for cardiovascular mortality comparing men versus women in individuals without type 2 diabetes mellitus [HR: 1.94; 95% confidence interval (CI) 1.63 to 2.32; p < 0.001]. In individuals with type 2 diabetes mellitus, however, further adjustment for lipoprotein(a) led to an increased risk for cardiovascular mortality in men and a decreased risk in women resulting in a statistically significant difference between men and women (HR: 1.53; 95% CI 1.04 to 2.24; p = 0.029). CONCLUSIONS: Women are described to have a stronger relative increase in cardiovascular mortality than men when comparing individuals with and without type 2 diabetes mellitus. Higher lipoprotein(a) concentrations in women with type 2 diabetes mellitus than in men with type 2 diabetes mellitus might partially explain this finding.

Utility of Genetically Predicted Lp(a) (Lipoprotein [a]) and ApoB Levels for Cardiovascular Risk Assessment.

BACKGROUND: Current lipid guidelines suggest measurement of Lp(a) (lipoprotein[a]) and ApoB (apolipoprotein B) for atherosclerotic cardiovascular disease risk assessment. Polygenic risk scores (PRSs) for Lp(a) and ApoB may identify individuals unlikely to have elevated Lp(a) or ApoB and thus reduce such suggested testing. METHODS: PRSs were developed using least absolute shrinkage and selection operator regression among 273 222 and 356 958 UK Biobank participants of white British ancestry for Lp(a) and ApoB, respectively, and validated in separate sets of 60 771 UK Biobank and 15 050 European Prospective Investigation into Cancer and Nutrition-Norfolk participants. We then assessed the proportion of participants who, based on these PRSs, were unlikely to benefit from Lp(a) or ApoB measurements, according to current lipid guidelines. RESULTS: In the UK Biobank and European Prospective Investigation into Cancer and Nutrition-Norfolk cohorts, the area under the receiver operating curve for the PRS-predicted Lp(a) and ApoB to identify individuals with elevated Lp(a) and ApoB was at least 0.91 (95% CI, 0.90-0.92) and 0.74 (95% CI, 0.73-0.75), respectively. The Lp(a) PRS and measured Lp(a) showed comparable association with atherosclerotic cardiovascular disease incidence, whereas the ApoB PRS was in general less predictive of atherosclerotic cardiovascular disease risk than measured ApoB. In the context of the European Society of Cardiology/European Atherosclerosis Society lipid guidelines, at a 95% sensitivity to identify individuals with elevated Lp(a) and ApoB levels, at least 54% of Lp(a) and 24% of ApoB testing could be reduced by prescreening with a PRS while maintaining a low false-negative rate. CONCLUSIONS: A substantial proportion of suggested testing for elevated Lp(a) and a modest proportion of testing for elevated ApoB could potentially be reduced by prescreening individuals with PRSs.

Lipoprotein(a) levels and risk of abdominal aortic aneurysm in the Women's Health Initiative.

OBJECTIVE: Few studies have prospectively examined the associations of lipoprotein(a) [Lp(a)] levels with the risk of abdominal aortic aneurysm (AAA), especially in women. Accounting for commonly recognized risk factors, we investigated the baseline Lp(a) levels and the risk of AAA among postmenopausal women participating in the ongoing national Women's Health Initiative. METHODS: Women's Health Initiative participants with baseline Lp(a) levels available who were beneficiaries of Medicare parts A and B fee-for-service at study enrollment or who had aged into Medicare at any point were included. Participants with missing covariate data or known AAA at baseline were excluded. Thoracic aneurysms were excluded owing to the different pathophysiology. The AAA cases and interventions were identified using the International Classification of Diseases, 9th and 10th revision, codes and Current Procedural Terminology codes from claims data. Hazard ratios were computed using Cox proportional hazard models according to the quintiles of Lp(a). RESULTS: The mean age of the 6615 participants included in the analysis was 65.3 years. Of the 6615 participants, 66.6% were non-Hispanic white, 18.9% were black, 7% were Hispanic and 4.7% were Asian/Pacific Islander. Compared with the participants in the lowest Lp(a) quintile, those in higher quintiles were more likely to be overweight, black, and former or current smokers, to have hypertension, hyperlipidemia, and a history of cardiovascular disease, and to use menopausal hormone therapy and statins. During 65,476 person-years of follow-up, with a median of 10.4 years, 415 women had been diagnosed with an AAA and 36 had required intervention. More than one half had required intervention for a ruptured AAA. We failed to find a statistically significant association between Lp(a) levels and incident AAA. Additional sensitivity analyses stratified by race, with exclusion of statin users and alternative categorizations of Lp(a) using log-transformed levels, tertiles, and a cutoff of >50 mg/dL, were conducted, which did not reveal any significant associations. CONCLUSIONS: We found no statistically significant association between Lp(a) levels and the risk of AAA in a large and well-phenotyped sample of postmenopausal women. Women with high Lp(a) levels were more likely to be overweight, black, and former or current smokers, and to have hypertension, hyperlipidemia, and a history of cardiovascular disease, or to use hormone therapy and statins compared with those with lower Lp(a) levels. These findings differ from previous prospective, case-control, and meta-analysis studies that had supported a significant relationship between higher Lp(a) levels and an increased risk of AAA. Differences in the association could have resulted from study limitations or sex differences.