Median Lipoprotein Research Articles

PCSK9 inhibitors in real life-Cardiometabolic risk management in dyslipidemic patients in Vienna.

Proprotein convertase subtilisin kexin type9 (PCSK9) inhibitors have emerged as important therapeutic options for patients unable to achieve the low-density lipoprotein cholesterol (LDL‑C) target or to tolerate alternative lipid-lowering agents. The aim of this study was to investigate the efficacy of PCSK9 inhibitor treatment in tertiary routine care, by determining the percentage of patients reaching individual LDL‑C target levels 1 year after treatment initiation. Patients routinely started on PCSK9 inhibitors at our lipid clinic between 2017 and 2020 were retrospectively analyzed. Attainment of the LDL‑C target, utilization of follow-ups, cardiovascular events and effects on laboratory parameters were investigated. In this study 347 patients were included, with the majority managed in secondary prevention (94.5%). The LDL‑C target was achieved by 44.9% after ca. 14months, with differences between statin users and non-users (51.0% vs. 22.7%; p < 0.001). The median LDL‑C decreased from 126.00 mg/dL at baseline to 48 mg/dL (-61.6%; -77.00 mg/dL; p < 0.001) after ~2months and to 60 mg/dL (-52.9%; -59.00 mg/dL; p < 0.001) after ~14months. Median lipoprotein(a) levels decreased significantly from 184.0 nmol/L to 165.5 nmol/L (-25.9%; -25.5 nmol/L; p = 0.001) after ~2months, whereas no effects on creatine kinase, amylase and lipase were detectable. Of the patients 15% utilized 4follow-ups. The PCSK9 inhibitor intolerance occurred in 3.5% of patients. With the effect of LDL-lowering remaining constant over 14months, PCSK9 inhibitor treatment showed effective and sustainable LDL‑C lowering in amajority of patients in secondary prevention, bringing them closer to the recommended LDL‑C goal, particularly those under concomitant statin medication. Treatment with PCSK9 inhibitors appears to be well-tolerated, confirming data from clinical trials in real life.

Genetics and Pathophysiological Mechanisms of Lipoprotein(a)-Associated Cardiovascular Risk.

Elevated lipoprotein(a) is a genetically transmitted codominant trait that is an independent risk driver for cardiovascular disease. Lipoprotein(a) concentration is heavily influenced by genetic factors, including LPA kringle IV-2 domain size, single-nucleotide polymorphisms, and interleukin-1 genotypes. Apolipoprotein(a) is encoded by the LPA gene and contains 10 subtypes with a variable number of copies of kringle -2, resulting in >40 different apolipoprotein(a) isoform sizes. Genetic loci beyond LPA, such as APOE and APOH, have been shown to impact lipoprotein(a) levels. Lipoprotein(a) concentrations are generally 5% to 10% higher in women than men, and there is up to a 3-fold difference in median lipoprotein(a) concentrations between racial and ethnic populations. Nongenetic factors, including menopause, diet, and renal function, may also impact lipoprotein(a) concentration. Lipoprotein(a) levels are also influenced by inflammation since the LPA promoter contains an interleukin-6 response element; interleukin-6 released during the inflammatory response results in transient increases in plasma lipoprotein(a) levels. Screening can identify elevated lipoprotein(a) levels and facilitate intensive risk factor management. Several investigational, RNA-targeted agents have shown promising lipoprotein(a)-lowering effects in clinical studies, and large-scale lipoprotein(a) testing will be fundamental to identifying eligible patients should these agents become available. Lipoprotein(a) testing requires routine, nonfasting blood draws, making it convenient for patients. Herein, we discuss the genetic determinants of lipoprotein(a) levels, explore the pathophysiological mechanisms underlying the association between lipoprotein(a) and cardiovascular disease, and provide practical guidance for lipoprotein(a) testing.

High Lipoprotein(a) May Explain One-Quarter of Clinical Familial Hypercholesterolemia Diagnoses in Danish Lipid Clinics.

Cholesterol carried in lipoprotein(a) adds to measured low-density lipoprotein cholesterol (LDL-C) and may therefore drive some diagnoses of clinical familial hypercholesterolemia (FH). We investigated plasma lipoprotein(a) in individuals referred to Danish lipid clinics and evaluated the effect of plasma lipoprotein(a) on a diagnosis of FH. Individuals referred to 15 Danish lipid clinics who were suspected of having FH according to nationwide referral criteria were recruited between September 1, 2020 and November 30, 2021. All individuals were classified according to the Dutch Lipid Clinical Network criteria for FH before and after LDL-C was adjusted for 30% cholesterol content in lipoprotein(a). We calculated the fraction of individuals fulfilling a clinical diagnosis of FH partly due to elevated lipoprotein(a). We included a total of 1166 individuals for analysis, of whom 206 fulfilled a clinical diagnosis of FH. Median lipoprotein(a) was 15 mg/dL (29 nmol/L) in those referred and 28% had lipoprotein(a) greater than or equal to 50 mg/dL (105 nmol/L), while 2% had levels greater than or equal to 180 mg/dL (389 nmol/L). We found that in 27% (55/206) of those fulfilling a clinical diagnosis of FH, this was partly due to high lipoprotein(a). Elevated lipoprotein(a) was common in individuals referred to Danish lipid clinics and in one-quarter of individuals who fulfilled a clinical diagnosis of FH, this was partly due to elevated lipoprotein(a). These findings support the notion that the LPA gene should be considered an important causative gene in patients with clinical FH and further support the importance of measuring lipoprotein(a) when diagnosing FH as well as for stratification of cardiovascular risk.

Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests.

Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system using mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (MACE). The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndrome. We compared risk of a MACE in the placebo group and MACE risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by Siemens N-latex nephelometric immunoassay (IA-mass; mg/dL), Roche Tina-Quant turbidimetric immunoassay (IA-molar; nmol/L), and a noncommercial mass spectrometry-based test (MS; nmol/L). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay. Among 11 970 trial participants with results from all 3 tests, baseline median (Q1, Q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/L for IA-mass, IA-molar, and MS, respectively. The strongest correlation was between IA-molar and MS (r=0.990), with nominally weaker correlations between IA-mass and MS (r=0.967) and IA-mass and IA-molar (r=0.972). Relationships of lipoprotein(a) with MACE risk in the placebo group were nearly identical with each test, with estimated cumulative incidences differing by ≤0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol levels (all spline P≤0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the 3 tests, with estimated treatment hazard ratios differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all 3 tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles. In patients with recent acute coronary syndrome, 3 lipoprotein(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Lipoprotein(a) and carotid intima-media thickness in children with familial hypercholesterolaemia in the Netherlands: a 20-year follow-up study

Elevated lipoprotein(a) and familial hypercholesterolaemia are both independent risk conditions for cardiovascular disease. Although signs of atherosclerosis can be observed in children with familial hypercholesterolaemia, it is unknown whether elevated lipoprotein(a) is an additional risk factor for atherosclerosis in these young patients. Therefore, we aimed to assess the contribution of lipoprotein(a) concentrations to arterial wall thickening (as measured by carotid intima-media thickness) in children with familial hypercholesterolaemia who were followed up into adulthood. We conducted a 20-year follow-up study of 214 children (aged 8-18 years) with heterozygous familial hypercholesterolaemia who were randomly assigned in a statin trial in Amsterdam (Netherlands) between Dec 7, 1997, and Oct 4, 1999. At baseline, and at 2, 10, and 20 years thereafter, blood samples were taken and carotid intima-media thickness was measured. Linear mixed-effects models were used to evaluate the association between lipoprotein(a) and carotid intima-media thickness during follow-up. We adjusted for sex, age, corrected LDL-cholesterol, statin use, and BMI. Our study population comprised 200 children who had a carotid intima-media thickness measurement and a measured lipoprotein(a) concentration from at least one visit available. Mean age at baseline was 13·0 years (SD 2·9), 106 (53%) children were male, and 94 (47%) were female. At baseline, median lipoprotein(a) concentration was 18·5 nmol/L (IQR 8·7-35·5) and mean carotid intima-media thickness was 0·4465 mm (SD 0·0496). During follow-up, higher lipoprotein(a) concentrations contributed significantly to progression of carotid intima-media thickness (β adjusted 0·0073 mm per 50 nmol/L increase in lipoprotein(a) [95% CI 0·0013-0·0132]; p=0·017). Our findings suggest that lipoprotein(a) concentrations contribute significantly to arterial wall thickening in children with familial hypercholesterolaemia who were followed-up until adulthood, suggesting that lipoprotein(a) is an independent and additional risk factor for early atherosclerosis in those already at increased risk. Lipoprotein(a) measurement in young patients with familial hypercholesterolaemia is crucial to identify those at potentially highest risk for cardiovascular disease. Silence Therapeutics.

Lipoprotein(a) and the Risk for Recurrent Atherosclerotic Cardiovascular Events Among Adults With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study

Many adults with chronic kidney disease (CKD) and atherosclerotic cardiovascular disease (ASCVD) have high lipoprotein(a) levels. It is unclear whether high lipoprotein(a) levels confer an increased risk for recurrent ASCVD events in this population. We estimated the risk for recurrent ASCVD events associated with lipoprotein(a) in adults with CKD and prevalent ASCVD. Observational cohort study. We included 1,439 adults with CKD and prevalent ASCVD not on dialysis enrolled in the Chronic Renal Insufficiency Cohort study between 2003 and2008. Baseline lipoprotein(a) mass concentration, measured using a latex-enhanced immunoturbidimetric assay. Recurrent ASCVD events (primary outcome), kidney failure, and death (exploratory outcomes) through2019. We used Cox proportional-hazards regression models to estimate adjusted HR (aHRs) and 95% CIs. Among participants included in the current analysis (mean age 61.6 years, median lipoprotein(a) 29.4 mg/dL [25th-75th percentiles 9.9-70.9 mg/dL]), 641 had a recurrent ASCVD event, 510 developed kidney failure, and 845 died over a median follow-up of 6.6 years. The aHR for ASCVD events associated with 1 standard deviation (SD) higher log-transformed lipoprotein(a) was 1.04 (95% CI, 0.95-1.15). In subgroup analyses, 1 SD higher log-lipoprotein(a) was associated with an increased risk for ASCVD events in participants without diabetes (aHR, 1.23; 95% CI, 1.02-1.48), but there was no evidence of an association among those with diabetes (aHR, 0.99; 95% CI, 0.88-1.10, P comparing aHRs=0.031). The aHR associated with 1 SD higher log-lipoprotein(a) in the overall study population was 1.16 (95% CI, 1.04-1.28) for kidney failure and 1.02 (95% CI, 0.94-1.11) for death. Lipoprotein(a) was not available in molar concentration. Lipoprotein(a) was not associated with the risk for recurrent ASCVD events in adults with CKD, although it was associated with a risk for kidney failure.

Lipoprotein(a)-related cardiovascular and all-cause mortalities in Korean adults.

There are inconsistent results on the association between lipoprotein(a) and mortality-related outcomes due to a lack of evidence from large-scale observational studies of Asians. This study aims to evaluate the effects of lipoprotein(a) on mortality-related outcomes in the Korean population. This cohort study included 275 430 individuals (mean age: 38 years; 50.1% men) enrolled in the Kangbuk Samsung Health Study between 2003 and 2016. The median follow-up period was 6.6 years. Cox proportional hazards analysis was used to estimate the adjusted hazard ratios (HRs) for evaluating mortality risk based on lipoprotein(a) levels and specific lipoprotein(a) categories. The median lipoprotein(a) value was 18.5 mg/dL, and the proportion of lipoprotein(a) ≥50 mg/dL was 12.8%. Multivariable Cox regression analysis showed that the group with lipoprotein(a) ≥50 mg/dL had a significantly increased risk of cardiovascular mortality (HR[95% CI]: 1.83[1.26, 2.64]) and all-cause mortality (1.20[1.03, 1.41]) than the group with lipoprotein(a) < 50 mg/dL without increased risk of cancer mortality (1.05[0.81, 1.34]). The relationship between lipoprotein(a) and cardiovascular mortality was significant regardless of low-density lipoprotein cholesterol. Specifically, lipoprotein(a) ≥100 mg/dL was associated with more than twice as increased a risk of cardiovascular mortality (2.45[1.12, 5.34]) than lipoprotein(a) < 10 mg/dL. In subgroup analyses, there was an interaction in the relationships between the two lipoprotein(a) categories and cardiovascular mortality for only high-density lipoprotein cholesterol. High lipoprotein(a) concentration is an independent predictor of cardiovascular mortality in the Korean population, regardless of low-density lipoprotein cholesterol levels.

Abstract 15650: Relationship Between Lipoprotein (a) and Aortic Vulnerable Plaques Detected by Non-Obstructive General Angioscopy

Background: Although atherosclerotic disease including myocardial infarction had decreased with lipid-lowering therapy for LDL cholesterol, atherosclerotic risk factors as residual risks without low-density lipoprotein are pointed out. Especially, lipoprotein (a) had been reported as one of the cardiovascular risks. Non-obstructive general angioscopy (NOGA) can meticulously visualize directly aortic atherosclerosis. NOGA-derived aortic vulnerable plaques had been reported to be related to future cardiovascular events. However, the relationships between serum lipoprotein (a) value and NOGA-derived aortic plaques had not been fully investigated yet. Methods and Results: We investigated consecutive 165 cases with coronary artery disease evaluated for the aorta by NOGA. Atherosclerotic lesions of the aorta were screened using NOGA immediately after coronary arteriography. NOGA examination evaluated the presence of aortic ruptured plaques which were "puff-chandelier rupture" appearance as previously reported. The mean age was 68 years and the median lipoprotein (a) value was 16 [9-27]. The median number of plaque ruptures was 1 [0-3], and 60% of cases had at least one plaque rupture. In a logistic regression analysis for the presence of aortic plaque rupture, the serum lipoprotein (a) value was associated with NOGA-derived aortic plaque rupture (odds ratio, 1.01 [1.0-1.03], p &lt; 0.05). The study patients were divided into three groups according to the tertile of serum lipoprotein (a) value [1st tertile: 0-11 mg/dl, 2nd tertile: 12-24 mg/dl, 3rd tertile 25 mg/dl &lt;], the first tertile had the lowest prevalence of plaque rupture (the presence of plaque rupture: first tertile 50%, second tertile 71%, third tertile 72%, p = 0.03). Conclusion: Serum lipoprotein (a) value was related to the presence of the aortic plaque rupture. Further studies are needed to elucidate the effect of the low lipoprotein (a) on the prevention of aortic vulnerable plaques.

Lipoprotein(a) in progressive coronary artery disease: beyond classical cardiovascular risk parameters

Abstract Introduction Classical primary preventive cardiovascular disease (CVD) risk algorithms, such as the Framingham risk score and the widely used QRISK score in the UK, predate large-scale deep-phenotyped biomedical research resources. There is therefore the opportunity to identify novel predictors. In addition, whilst CVD risk profiling is well studied in the context of primary prevention, there is a paucity of data examining risk in regard to secondary prevention. Purpose To identify independent predictors of repeat coronary artery revascularisation, following index coronary angioplasty. Methods The UK Biobank is a large prospective multicentre study which recruited over 500,000 participants in the UK aged 37–73 years at entry between 2006–2010. Data are derived from an array of physical measurements, self-reported measures and biological samples, together with longitudinal linkage to hospital inpatient records and death registries. Procedural codes were used to identify patients who had undergone first coronary angioplasty from 2006 onwards. Repeat revascularisation (RR) was defined as angioplasty or bypass grafting occurring at least 9 months after the index angioplasty, in order to preclude instances of staged revascularisation and in-stent restenosis. Data were censored at January 2021 or date of death as appropriate. Results A total of 12,853 participants underwent a first coronary angioplasty during the study period, with 1,394 (10.8%) requiring RR over a median follow-up of 6.5 years. The average age was 64 years in the RR cohort and 1117 (80%) were male. Univariate analyses confirmed a number of established associations with RR, including for example diabetes mellitus and hypertension. Median lipoprotein(a) concentrations were 27.6 vs. 30.3nmol/L in the RR group, p=0.066. Cox regression analyses (n=7,216) incorporating 21 biometric and clinical parameters demonstrated that lipoprotein(a) &amp;gt;80nmol/L was one of six independent predictors of time to RR (HR 1.24, p=0.006), independent of other lipids. The strength and significance of this association persisted when the number of covariates was reduced to include only other lipids and classical cardiovascular risk parameters. LDL, HDL, and triglyceride levels were not significant predictors in this model. Conclusions Lipoprotein(a) is identified as a major independent driver of RR. However current European Society of Cardiology guidance does not recommend measurement of Lipoprotein(a) in the context of progressive coronary artery disease. Furthermore, it is known that strategies such as lifestyle advice and statins – recommended in all patients with established coronary artery disease - do no reduce lipoprotein(a), whilst niacin and PCSK9 inhibitors do have a significant effect. Indications for lipoprotein(a) measurement must therefore be broadened, so that specific treatments to lower it can be instituted in order to reduce the burden of progressive coronary artery disease. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Herefordshire Heart Fund

Lipoprotein(a) in the Korean Pediatric Population Visiting Local Clinics and Hospitals.

In this paper we investigate serum lipoprotein(a), an independent risk factor for cardiovascular disease in the Korean pediatric population. Visiting local clinics and hospitals, 600 lipoprotein(a) tests were performed on 416 Korean children and adolescents (124 boys and 292 girls), with a median age of 11.1 years (interquartile range, IQR, 9.8–13.9). The median lipoprotein(a) level was 21.5 nmol/L (IQR, 8.2–51.7). Among the 416 patients, the 90th percentile value of the initial lipoprotein(a) measurement was 107.8 nmol/L. The proportion of patients with lipoprotein(a) ≥ 100 nmol/L was 11.3%. The lipoprotein(a) level and the proportion of patients with lipoprotein(a) ≥ 100 nmol/L were not significantly different among sex, or age group. Among the 416 patients, 122 (29.3%, 21 boys and 101 girls) underwent at least two follow-up lipoprotein(a) measurements. The median follow-up period was 6.7 months (IQR, 5.5–11.8). The median lipoprotein(a) level across the 122 patients was 25 nmol/L (IQR 10.0–72.0). Among those patients, seven (5.7%) experienced an increase in serum lipoprotein(a) to ≥100 nmol/L during follow-up measurements. Further studies are needed in the Korean pediatric population in order to clarify the clinical significance of this change long-term.

Repeat revascularisation following PCI in the UK Biobank prospective cohort study: incidence, independent predictors and prognostic impact

Abstract Introduction Data from the SYNTAX and EXCEL trials have previously demonstrated increased morbidity and mortality following repeat revascularisation (RR). However real-world RR rates following index PCI are poorly defined, particularly in the 'late' context of restenosis of bystander disease and de novo lesions. Purpose To identify independent predictors of RR and evaluate its prognostic impact in an unselected cohort of patients following first PCI. Methods The UK Biobank is a large prospective multicentre study which recruited over 500,000 participants in the UK aged 37–73 years at entry between 2006–2010. Data are derived from an array of physical measurements, self-reported measures and biological samples, together with longitudinal linkage to hospital inpatient records and death registries. Procedural codes (OPCS-4) were used to identify patients who had undergone first PCI from 2006 onwards. RR was defined as PCI or CABG occurring at least 9 months after the index PCI, in order to preclude instances of staged revascularisation and in-stent restenosis. Data were censored at January 2021 or date of death as appropriate. Non-parametric tests are used throughout. Results A total of 12,853 participants underwent a first PCI during the study period, with 1,394 (10.8%) requiring RR over a median follow-up of 6.5 years. Of these, 1188 underwent PCI whilst 206 were elected to CABG. The average age was 64 years in the RR cohort and 1117 (80%) were male. Univariate analyses confirmed a number of established associations with RR, including for example diabetes mellitus and hypertension. Median lipoprotein(a) concentrations were 27.6 vs. 30.3nmol/L in the RR group, p=0.066. Cox regression analyses incorporating 21 biometric and clinical parameters demonstrated that lipoprotein(a) was an independent predictor of time to RR, independent of other lipids (Table 1). The strength of this association persisted when the number of covariates was reduced to include only other lipids and classical cardiovascular risk parameters. In Kaplan-Meier analyses, RR was associated with lower all-cause mortality (Figure 1). Further multivariate time-to-event analyses confirmed this association (HR 0.59, 95% CI 0.47–0.75, p&amp;lt;0.001). In separate models examining PCI and CABG as distinct modalities of RR, both were independently associated with prognostic benefit (HR 0.61, p&amp;lt;0.001 and HR 0.48, p&amp;lt;0.05 respectively). Conclusions Lipoprotein(a) is identified as a major independent driver of RR. In contrast to recent trial data focussing on left main stem and multivessel disease, unselected patients undergoing RR 9 or more months following index PCI attain prognostic benefit as assessed in multivariate analyses. The findings support an invasive approach, whether with PCI or CABG, in progressive coronary artery disease following initial PCI. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): 1. The Herefordshire Heart Fund, UK. 2. Postgraduate Medical Bursary, Wye Valley NHS Trust, UK. Table 1Figure 1

Familial hypercholesterolemia in Mexico: Initial insights from the national registry

BackgroundFamilial hypercholesterolemia (FH) remains underdiagnosed and undertreated. ObjectiveReport the results of the first years (2017-2019) of the Mexican FH registry. MethodsThere are 60 investigators, representing 28 federal states, participating in the registry. The variables included are in accordance with the European Atherosclerosis Society (EAS) FH recommendations. ResultsTo date, 709 patients have been registered, only 336 patients with complete data fields are presented. The mean age is 50 (36-62) years and the average time since diagnosis is 4 (IQR: 2-16) years. Genetic testing is recorded in 26.9%. Tendon xanthomas are present in 43.2%. The prevalence of type 2 diabetes is 11.3% and that of premature CAD is 9.8%. Index cases, male gender, hypertension and smoking were associated with premature CAD. The median lipoprotein (a) level is 30.5 (IQR 10.8-80.7) mg/dl. Statins and co-administration with ezetimibe were recorded in 88.1% and 35.7% respectively. A combined treatment target (50% reduction in LDL-C and an LDL-C <100 mg/dl) was achieved by 13.7%. Associated factors were index case (OR 3.6, 95%CI 1.69-8.73, P = .002), combination therapy (OR 2.4, 95%CI 1.23-4.90, P = .011), type 2 diabetes (OR 2.8, 95%CI 1.03-7.59, P = .036) and age (OR 1.023, 95%CI 1.01-1.05, P = .033). ConclusionThe results confirm late diagnosis, a lower than expected prevalence and risk of ASCVD, a higher than expected prevalence of type 2 diabetes and undertreatment, with relatively few patients reaching goals. Recommendations include, the use of combination lipid lowering therapy, control of comorbid conditions and more frequent genetic testing in the future.

Lp(a) (Lipoprotein[a]) Concentrations and Incident Atherosclerotic Cardiovascular Disease: New Insights From a Large National Biobank.

Lp(a) (lipoprotein[a]) concentrations are associated with atherosclerotic cardiovascular disease (ASCVD), and new therapies that enable potent and specific reduction are in development. In the largest study conducted to date, we address 3 areas of uncertainty: (1) the magnitude and shape of ASCVD risk conferred across the distribution of lipoprotein(a) concentrations; (2) variation of risk across racial and clinical subgroups; (3) clinical importance of a high lipoprotein(a) threshold to guide therapy. Approach and Results: Relationship of lipoprotein(a) to incident ASCVD was studied in 460 506 middle-aged UK Biobank participants. Over a median follow-up of 11.2 years, incident ASCVD occurred in 22 401 (4.9%) participants. Median lipoprotein(a) concentration was 19.6 nmol/L (25th-75th percentile 7.6-74.8). The relationship between lipoprotein(a) and ASCVD appeared linear across the distribution, with a hazard ratio of 1.11 (95% CI, 1.10-1.12) per 50 nmol/L increment. Substantial differences in concentrations were noted according to race-median values for white, South Asian, black, and Chinese individuals were 19, 31, 75, and 16 nmol/L, respectively. However, risk per 50 nmol/L appeared similar-hazard ratios of 1.11, 1.10, and 1.07 for white, South Asian, and black individuals, respectively. A high lipoprotein(a) concentration defined as ≥150 nmol/L was present in 12.2% of those without and 20.3% of those with preexisting ASCVD and associated with hazard ratios of 1.50 (95% CI, 1.44-1.56) and 1.16 (95% CI, 1.05-1.27), respectively. Lipoprotein(a) concentrations predict incident ASCVD among middle-aged adults within primary and secondary prevention contexts, with a linear risk gradient across the distribution. Concentrations are variable across racial subgroups, but the associated risk appears similar.

Lipoprotein(a) and long-term recurrent infarction after an episode of ST-segment elevation acute myocardial infarction.

In established ischemic heart disease, the relationship between lipoprotein(a) and new cardiovascular events showed contradictory results. Our aim was to assess the relationship between lipoprotein(a) and very long-term recurrent myocardial infarction (MI) after an index episode of ST-segment elevation acute myocardial infarction (STEMI). We included 435 consecutive STEMI patients discharged from October 2000 to June 2003 in a single teaching center. The relationship between lipoprotein(a) at discharge and recurrent MI was evaluated through negative binomial regression and Cox regression analysis. The mean age was 65 years (55-74 years), 25.5% were women, 34.7% were diabetic, and 66% had a MI of anterior location. Fibrinolysis, rescue, or primary angioplasty was performed in 215 (49.4%), 19 (4.4%), and 18 (4.1%) patients, respectively. The median lipoprotein(a) was 30.4 mg/dL (12-59.4 mg/dL). After a median follow-up of 9.6 years (4.1-15 years), 180 (41.4%) deaths and 187 MI in 133 (30.6%) patients were recorded. After a multivariate adjustment, the risk gradient of lipoprotein(a) showed a neutral effect along most of the continuum and only extreme higher values identified those at higher risk of recurrent MI (P = 0.020). Those with lipoprotein(a) values >95th percentile (≥135 mg/dL) showed a higher risk of recurrent MI (incidence rate ratio, 2.34; 95% confidence interval, 1.37-4.02; P = 0.002). Lipoprotein(a) was not related to the risk of mortality (P = 0.245). After an episode of STEMI, only extreme high values of lipoprotein(a) were associated with an increased risk of long-term recurrent MI.

Peripheral Artery Disease and Venous Thromboembolic Events After Acute Coronary Syndrome: Role of Lipoprotein(a) and Modification by Alirocumab: Prespecified Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial.

Patients with acute coronary syndrome are at risk for peripheral artery disease (PAD) events and venous thromboembolism (VTE). PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C) levels. Our objective was to ascertain whether PCSK9 inhibition reduces the risk of PAD events or VTE after acute coronary syndrome, and if such effects are related to levels of lipoprotein(a) or LDL-C. This was a prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome), which was conducted in 18 924 patients with recent acute coronary syndrome on intensive or maximum-tolerated statin treatment who were randomized to the PCSK9 inhibitor alirocumab or placebo. In a prespecified analysis, PAD events (critical limb ischemia, limb revascularization, or amputation for ischemia) and VTE (deep vein thrombosis or pulmonary embolism) were assessed. LDL-C was corrected (LDL-Ccorrected) for cholesterol content in lipoprotein(a). At baseline, median lipoprotein(a) and LDL-Ccorrected were 21 and 75 mg/dL, respectively; with alirocumab, median relative reductions were 23.5% and 70.6%, respectively. PAD events and VTE occurred in 246 and 92 patients, respectively. In the placebo group, risk of PAD events was related to baseline quartile of lipoprotein(a) (Ptrend=0.0021), and tended to associate with baseline quartile of LDL-Ccorrected (Ptrend=0.06); VTE tended to associate with baseline quartile of lipoprotein(a) (Ptrend=0.06), but not LDL-Ccorrected (Ptrend=0.85). Alirocumab reduced risk of PAD events (hazard ratio [HR], 0.69 [95% CI, 0.54-0.89]; P=0.004), with nonsignificantly fewer VTE events (HR, 0.67 [95% CI, 0.44-1.01]; P=0.06). Reduction in PAD events with alirocumab was associated with baseline quartile of lipoprotein(a) (Ptrend=0.03), but not LDL-Ccorrected (Ptrend=0.50). With alirocumab, the change from baseline to Month 4 in lipoprotein(a), but not LDL-Ccorrected, was associated with the risk of VTE and the composite of VTE and PAD events. In statin-treated patients with recent acute coronary syndrome, risk of PAD events is related to lipoprotein(a) level and is reduced by alirocumab, particularly among those with high lipoprotein(a). Further study is required to confirm whether risk of VTE is related to lipoprotein(a) level and its reduction with alirocumab. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Effect of Evolocumab on Non-High-Density Lipoprotein Cholesterol, Apolipoprotein B, and Lipoprotein(a): A Pooled Analysis of Phase 2 and Phase 3 Studies.

BackgroundDyslipidemia guidelines recommend non‐high‐density lipoprotein cholesterol (non‐HDL‐C) and apolipoprotein B (ApoB) as additional targets of therapy and consider lipoprotein(a) a significant cardiovascular risk marker. The current analysis evaluates the effects of evolocumab on these parameters in various patient populations over time.Methods and ResultsData from 7690 patients, 4943 of whom received at least 1 dose of evolocumab, in 15 phase 2 and phase 3 studies with a duration ranging from 12 weeks to 5 years were pooled based on study length, patient population, and ezetimibe or placebo comparator groups. Patients could receive intensive statin therapy but not in the statin intolerance and monotherapy studies. The effects of evolocumab on percent change from baseline for non‐HDL‐C, ApoB, and lipoprotein(a) and achievement of treatment goals for non‐HDL‐C and ApoB were examined. Compared with placebo, evolocumab at both approved dosing regimens substantially reduced mean non‐HDL‐C (Q2W dose: −49% to −56%, monthly dose: −48% to −52%), mean ApoB (Q2W dose: −46% to −52%, monthly dose: −40% to −48%), and median lipoprotein(a) (Q2W dose: −22% to −38%, monthly dose: −20% to −33%) at 12 weeks. Effects on all 3 parameters persisted over 5 years. Lipid‐lowering effects were consistent among the patient populations examined (hypercholesterolemia/mixed dyslipidemia, statin intolerance, heterozygous familial hypercholesterolemia, and type 2 diabetes mellitus).ConclusionsIn this pooled analysis, evolocumab substantially reduced non‐HDL‐C, ApoB, and lipoprotein(a) compared with placebo. The effect was consistent and maintained in various patient populations over 5 years.

Alirocumab efficacy and safety by race and ethnicity: Analysis from 3 ODYSSEY phase 3 trials

Differences in lipid and cardiovascular risk profiles have been observed in African-American/black (AA/B), white (W), and Hispanic/Latino (H/L) individuals. Efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, may vary by race and ethnicity and has not been analyzed. This post hoc analysis evaluated alirocumab efficacy and safety vs control in 3 pooled ODYSSEY phase 3 trials (COMBO I, COMBO II, and LONG TERM) by race (AA/B [n=154] vs W [n=1982]) and ethnicity (H/L [n=174] vs non-H/L [n=3149]). Patients with elevated low-density lipoprotein cholesterol (LDL-C) despite maximally tolerated statin received alirocumab (75mg up to 150mg every 2weeks [COMBO I & II] or 150mg every 2weeks [LONG TERM]) or control (placebo [COMBO I and LONG TERM] or ezetimibe [COMBO II]). At baseline, LDL-C levels were similar across treatment groups; median lipoprotein(a) levels were higher in AA/B (33.0-120.0mg/dL) vs W (7.1-66.3mg/dL) and lower in H/L (5.0-38.3mg/dL) vs non-H/L (7.7-69.0mg/dL). At week 24, alirocumab significantly reduced LDL-C vs control. Alirocumab also reduced lipoprotein(a) compared with control across the subgroups. Treatment-emergent adverse events were similar between alirocumab (68.9-85.0%) and control (70.6-82.4%) regardless of race and ethnicity. Alirocumab significantly reduced LDL-C and Lp(a) levels compared with control, regardless of race and ethnicity, with overall safety comparable to control across most of the racial and ethnic groups analyzed.

Prevalence of elevated lipoprotein(a) levels in Korean: A large population-based study

Background: Large population-based studies on lipoprotein(a) in Korea are rare. We aimed to evaluate lipoprotein(a) concentration among the Korean population, stratified by age and sex. Methods: Results were obtained through the laboratory information system of Green Cross Laboratories, one of the largest referral laboratories in South Korea. Lipoprotein(a) concentrations were evaluated in the Korean population stratified by age and sex. Results: During the one-year study period, 14,395 lipoprotein(a) measurements were obtained from 14,158 Korean adults (8,418 men and 5,740 women) from 82 hospitals and/or local clinics. The median (Interquartile Range, IQR) lipoprotein(a) concentration of the total population was 19.6 (9.0-47.6) nmol/L. Median (IQR) lipoprotein(a) concentrations were higher in women (23.3, 10.854.5 nmol/L) than in men (17.4, 8.0-42.7 nmol/L, P<0.0001). The correlation coefficient r between lipoprotein(a) concentration and age was 0.1632 (P<0.0001). Among 14,395 lipoprotein(a) measurements, 15.3% (n=2,209) of results were higher than 75.0 nmol/L, the cut-off value for increased risk for cardiovascular diseases in Caucasians. Conclusions: This study provides basic information regarding expected values for lipoprotein(a) concentration in the Korean population.

Evaluating the Potential Association Between Lipoprotein(a) and Atherosclerosis (from the Mediators of Atherosclerosis Among South Asians Living in America Cohort)

We sought to report the distribution of Lp(a) levels in the Mediators of Atherosclerosis among South Asians Living in America cohort of participants who were free from clinical atherosclerotic cardiovascular disease (ASCVD) at baseline and to evaluate the cross-sectional association with atherosclerosis measured by coronary artery calcification (CAC) and carotid intima media thickness. Among 886 participants (mean [SD] age: 55.4 [9.4] years, 54% male), median lipoprotein (a) level was 17 (9, 33) mg/dl. Compared with the lowest quartile (9 mg/dl), subjects in the highest Lp(a) quartile (33 to 178 mg/dl) were more likely to be women (51% vs 37%, p <0.01) and had a higher mean (SD) total cholesterol (193 [37] mg/dl vs 181 [35] mg/dl, p <0.01). CAC was present in 42% and both the presence and degree of CAC was similar across Lp(a) quartiles (p = 0.58). Median Interquartile range (IQR) common and internal carotid intima-media thickness (IMT) thicknesses were 0.84 (0.73, 0.98) mm and 1.12 (0.95, 1.34) mm, respectively, and were also similar across Lp(a) quartiles. After adjustment for cardiovascular risk factors, Lp(a) quartile had no association with prevalent CAC (p = 0.98), internal carotid IMT (p = 0.46), or common carotid IMT (p = 0.97). Among South Asian Americans, mean Lp(a) levels were higher than previous reports among Whites, Hispanic/Latino, and Chinese-Americans but lower than in Blacks. Unlike findings from other race/ethnic groups, Lp(a) levels were not associated with atherosclerosis among South Asian Americans.

Lipoprotein(a) a Risk Factor for Venous Thrombosis and Pulmonary Embolism in Patients Younger Than 50 Years of Age

Introduction: Despite convincing evidence toward causal role of Lipoprotein(a) in occlusive arterial disease, the data is conflicting when it comes to venous thromboembolism (VTE) and pulmonary embolism (PE). Also it is not known if intervention to normalize Lipoprotein(a) will decrease risk of recurrent VTE and PE eliminating the need for life long anticoagulation. To our knowledge this isfirst data set report focusing on evaluating association between Lipoprotein(a) and VTE in patients younger than 50 years old. Methods: Inthis retrospective study, chart review was completed for twenty-six consecutive patients referred to hematology clinic with diagnosis of deep vein thrombosis (DVT) or PE in year 2017-2018 . Four patients older than 50 years old at the time of acute events were excluded. Lipoprotein(a) had only been measured in patients who had negative hypercoagulable work up with normal lipid panel but had obesity . Protein C, S and anti-thrombin were not measured if patients were already on anticoagulation. Serum level of Lipoprotein(a) greater than 75 nmol/L was considered to be elevated. Results: Total of 22 patients (18 females) were included in the data analysis. Nine patients had DVT, 5 patients had PE, and 8 patients had both DVT and PE. Median age was 34 (12-47). Lipoprotein(a) level was not checked on eight patients who had SLE (n=1), surgery (n=1), Factor V Leiden mutation (n=1), protein S deficiency (n=1), anti-phospholipid syndrome (n=2), prothrombin gene mutation (n=1), and one patient who had lost follow up. The median Lipoprotein(a) level was 107 (8-276). Serum Lipoprotein(a) was elevated in 8 out of the 14 screened patients (57%) with the median of 135 (107-276). Out of 8 patients with elevated Lipoprotein(a), only 1 patient had additional clinical risk factors for thrombosis (history of smoking, alcohol abuse, hypertriglyceridemia and elevated LDL). In an attempt to normalize Lipoprotein(a) level, 3 patients were started on niacin but only one tolerated maximum 1000 mg niacin daily which resulted in decrease in level but did not achieve normalization. Conclusion: This data suggests that elevated serum Lipoprotein(a) in females younger than 50 years old is associated with DVT/PE events. Further investigation is required to confirm this finding. At this time it is not known if attempt to normalize Lipoprotein(a) will prevent recurrent PE/DVT and eliminate need for long life anticoagulation in patients with unprovoked VTE who have elevated lipoprotein(a). DisclosuresPakbaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.