Lipoprotein(a) and Cardiovascular Disease Prevention across Diverse Populations.
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ABSTRACT:
SUBMITTER: Pearson K
PROVIDER: S-EPMC7584702 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Purpose of reviewThe primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on optimizing cardiovascular health and appropriate pharmacotherapy, a mainstay of which is low-density lipoprotein-cholesterol (LDL-C) lowering. Typically, statin therapy remains the first line approach. Advances in technology and understanding of lipid metabolism have facilitated the development of several novel therapeutic targets and medications within the last decade. This review focuses on medications recently approved by the U.S. Food and Drug Administration (FDA) for the reduction of LDL-C and ASCVD risk, as well as new therapies in the pipeline.Recent findingsNovel lipid therapies aim to lower risk of ASCVD by targeting reduction of atherogenic compounds, such as LDL, lipoprotein(a) (Lp(a)), and triglyceride-rich lipoproteins. Evolocumab and alirocumab, monoclonal antibody proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors which lower LDL-C by approximately 60%, have emerged as important therapies for use in patients with ASCVD as well as familial hypercholesterolemia (FH). Bempedoic acid, an ATP citrate lyase inhibitor, is an oral medication recently approved that can lower LDL-C by approximately 18% alone and 38% when combined with ezetimibe. Inclisiran, a small-interfering RNA (siRNA) molecule which inhibits the translation of PCSK9, is the most recently FDA-approved LDL-C lowering medication, and can reduce LDL-C by approximately 50% with twice yearly subcutaneous dosing. The cardiovascular outcome trials for bempedoic acid and inclisiran are still on-going. Evinacumab, a monoclonal antibody which targets angiopoietin-like protein 3 (ANGPTL3), has been approved for use in patients with homozygous FH. SiRNAs and anti-sense oligonucleotides (ASO) facilitating selective inhibition of the production of targeted proteins including Lp(a) and ANGLPTL3 are active areas of clinical investigation.SummaryRecently several novel LDL-C lowering medications have been approved. New therapeutic targets have been identified and present additional means of lowering LDL-C and other atherogenic compounds for patients who remain at high ASCVD risk.
| S-EPMC9543364 | biostudies-literature
Project description:ObjectiveTo estimate the potential cost effectiveness of a population-wide risk factor reduction programme aimed at preventing cardiovascular disease.DesignEconomic modelling analysis.SettingEngland and Wales. Population Entire population. Model Spreadsheet model to quantify the reduction in cardiovascular disease over a decade, assuming the benefits apply consistently for men and women across age and risk groups.Main outcome measuresCardiovascular events avoided, quality adjusted life years gained, and savings in healthcare costs for a given effectiveness; estimates of how much it would be worth spending to achieve a specific outcome.ResultsA programme across the entire population of England and Wales (about 50 million people) that reduced cardiovascular events by just 1% would result in savings to the health service worth at least £30m (€34m; $48m) a year compared with no additional intervention. Reducing mean cholesterol concentrations or blood pressure levels in the population by 5% (as already achieved by similar interventions in some other countries) would result in annual savings worth at least £80m to £100m. Legislation or other measures to reduce dietary salt intake by 3 g/day (current mean intake approximately 8.5 g/day) would prevent approximately 30,000 cardiovascular events, with savings worth at least £40m a year. Legislation to reduce intake of industrial trans fatty acid by approximately 0.5% of total energy content might gain around 570,000 life years and generate NHS savings worth at least £230m a year.ConclusionsAny intervention that achieved even a modest population-wide reduction in any major cardiovascular risk factor would produce a net cost saving to the NHS, as well as improving health. Given the conservative assumptions used in this model, the true benefits would probably be greater.
| S-EPMC3145836 | biostudies-literature
Project description:Aims:Lipoprotein(a) (Lp(a)) elevation is a causal risk factor for cardiovascular disease (CVD). It has however been suggested that elevated Lp(a) causes CVD mainly in individuals with high low-density lipoprotein cholesterol (LDL-C) levels. We hypothesized that the risk associated with high Lp(a) levels would largely be attenuated at low LDL-C levels. Methods and results:In 16 654 individuals from the EPIC-Norfolk prospective population study, and in 9448 individuals from the Copenhagen City Heart Study (CCHS) parallel statistical analyses were performed. Individuals were categorized according to their Lp(a) and LDL-C levels. Cut-offs were set at the 80th cohort percentile for Lp(a). Low-density lipoprotein cholesterol cut-offs were set at 2.5, 3.5, 4.5, and 5.5 mmol/L. Low-density lipoprotein cholesterol levels in the primary analyses were corrected for Lp(a)-derived LDL-C (LDL-Ccorr). Multivariable-adjusted hazard ratios were calculated for each category. The category with LDL-Ccorr <2.5 mmol/L and Lp(a) <80th cohort percentile was used as reference category. In the EPIC-Norfolk and CCHS cohorts, individuals with an Lp(a) ?80th percentile were at increased CVD risk compared with those with Lp(a) <80th percentile for any LDL-Ccorr levels ?2.5 mmol/L. In contrast, for LDL-Ccorr <2.5 mmol/L, the risk associated with elevated Lp(a) attenuated. However, there was no interaction between LDL-Ccorr and Lp(a) levels on CVD risk in either cohort. Conclusion:Lipoprotein(a) and LDL-C are independently associated with CVD risk. At LDL-C levels below <2.5 mmol/L, the risk associated with elevated Lp(a) attenuates in a primary prevention setting.
| S-EPMC6287703 | biostudies-literature
Project description:Numerous genetic and epidemiologic studies have demonstrated an association between elevated levels of lipoprotein(a) (Lp[a]) and cardiovascular disease. As a result, lowering Lp(a) levels is widely recognized as a promising strategy for reducing the risk of new-onset coronary heart disease, stroke, and heart failure. Lp(a) consists of a low-density lipoprotein-like particle with covalently linked apolipoprotein A (apo[a]) and apolipoprotein B-100, which explains its pro-thrombotic, pro-inflammatory, and pro-atherogenic properties. Lp(a) serum concentrations are genetically determined by the apo(a) isoform, with shorter isoforms having a higher rate of particle synthesis. To date, there are no approved pharmacological therapies that effectively reduce Lp(a) levels. Promising treatment approaches targeting apo(a) expression include RNA-based drugs such as pelacarsen, olpasiran, SLN360, and lepodisiran, which are currently in clinical trials. In this comprehensive review, we provide a detailed overview of RNA-based therapeutic approaches and discuss the recent advances and challenges of RNA therapeutics specifically designed to reduce Lp(a) levels and thus the risk of cardiovascular disease.
| S-EPMC10899152 | biostudies-literature
Project description:BackgroundThis study explored the longitudinal relationship of Lp(a) (lipoprotein[a]) and hypertension to cardiovascular outcomes in a large multiethnic cohort free of baseline cardiovascular disease.MethodsIndividuals from the MESA (Multi-Ethnic Study of Atherosclerosis; N=6674) were grouped as follows: group 1: Lp(a) <50 mg/dL and no hypertension; group 2: Lp(a) ≥50 mg/dL and no hypertension; group 3: Lp(a) <50 mg/dL and hypertension; and group 4: Lp(a) ≥50 mg/dL and hypertension. Kaplan-Meier curves and multivariable Cox proportional hazard models were used to assess the relationship of Lp(a) and hypertension with time to cardiovascular disease events.ResultsMean follow-up time was 13.9 (5.0) years and 809 participants experienced a cardiovascular disease event. A statistically significant interaction was found between Log[Lp(a)] and hypertension status (P=0.091). Compared with the reference group (Lp[a] <50 mg/dL and no hypertension), those with Lp[a] ≥50 mg/dL and no hypertension had no increased risk for cardiovascular disease events (hazard ratio, 1.09 [95% CI, 0.79-1.50]). However, those with Lp(a) <50 mg/dL and hypertension or Lp(a) ≥50 mg/dL and hypertension demonstrated a statistically significant increase in risk compared to the reference group (hazard ratio, 1.66 [95% CI, 1.39-1.98]) and (hazard ratio, 2.07 [95% CI, 1.63-2.62]), respectively. Among those with hypertension, Lp(a) was associated with a significant increase in cardiovascular disease risk (hazard ratio, 1.24 [95% CI, 1.01-1.53]).ConclusionsAlthough the major contribution to cardiovascular risk was hypertension, elevated Lp(a) significantly modified the association of hypertension with cardiovascular disease. More research is needed to understand mechanistic links among Lp(a), hypertension, and cardiovascular disease.
| S-EPMC9983733 | biostudies-literature
Project description:Lipid- and lipoprotein-modifying therapies have expanded substantially in the last 25 years, resulting in reduction in the incidence of major adverse cardiovascular events. However, no specific lipoprotein(a) [Lp(a)]-targeting therapy has yet been shown to reduce cardiovascular disease risk. Many epidemiological and genetic studies have demonstrated that Lp(a) is an important genetically determined causal risk factor for coronary heart disease, aortic valve disease, stroke, heart failure, and peripheral vascular disease. Accordingly, the need for specific Lp(a)-lowering therapy has become a major public health priority. Approximately 20% of the global population (1.4 billion people) have elevated levels of Lp(a) associated with higher cardiovascular risk, though the threshold for determining 'high risk' is debated. Traditional lifestyle approaches to cardiovascular risk reduction are ineffective at lowering Lp(a). To address a lifelong risk factor unmodifiable by non-pharmacological means, Lp(a)-lowering therapy needs to be safe, highly effective, and tolerable for a patient population who will likely require several decades of treatment. N-acetylgalactosamine-conjugated gene silencing therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotide targeting LPA, are ideally suited for this application, offering a highly tissue- and target transcript-specific approach with the potential for safe and durable Lp(a) lowering with as few as three or four doses per year. In this review, we evaluate the causal role of Lp(a) across the cardiovascular disease spectrum, examine the role of established lipid-modifying therapies in lowering Lp(a), and focus on the anticipated role for siRNA therapeutics in treating and preventing Lp(a)-related disease.
| S-EPMC8953457 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) is the most frequent genetic disorder resulting in increased low-density lipoprotein cholesterol (LDL-C) levels from childhood, leading to premature atherosclerotic cardiovascular disease (ASCVD) if left untreated. FH diagnosis is based on clinical criteria and/or genetic testing and its prevalence is estimated as being up to 1:300,000-400,000 for the homozygous and ~1:200-300 for the heterozygous form. Apart from its late diagnosis, FH is also undertreated, despite the available lipid-lowering therapies. In addition, elevated lipoprotein(a) (Lp(a)) (>50 mg/dL; 120 nmol/L), mostly genetically determined, has been identified as an important cardiovascular risk factor with prevalence rate of ~20% in the general population. Novel Lp(a)-lowering therapies have been recently developed and their cardiovascular efficacy is currently investigated. Although a considerable proportion of FH patients is also diagnosed with high Lp(a) levels, there is a debate whether these two entities are associated. Nevertheless, Lp(a), particularly among patients with FH, has been established as a significant cardiovascular risk factor. In this narrative review, we present up-to-date evidence on the pathophysiology, diagnosis, and treatment of both FH and elevated Lp(a) with a special focus on their association and joint effect on ASCVD risk.
| S-EPMC9693181 | biostudies-literature
Project description:The purpose of this review is to describe novel pharmacologic and nonpharmacologic preventive therapies, as well as new strategies to improve delivery of available therapies. Cardiovascular disease (CVD) is the leading cause of death worldwide, and prevention plays a critical role in curbing the global epidemic. Despite available treatment for tobacco addiction, platelet inhibition, blood pressure, and lipid lowering for reduction of atherosclerotic disease, significant gaps in treatment of total CVD remain. We review a range of new preventive treatment options, including drugs for tobacco cessation, platelet/thrombotic inhibition, lipid- and blood pressure-lowering; nonpharmacologic options such as left atrial appendage closure devices and caloric restriction; and strategies such as fixed-dose combination drugs, laboratory screening for drug tailoring, and community-based prevention programs. CVD preventive research continues to evolve and provide clinicians and patients with novel pharmacologic and nonpharmacologic therapies, including new preventive strategies.
| S-EPMC3911909 | biostudies-other
Project description:Lipoprotein(a) (Lp[a]) is a LDL-like particle consisting of an ApoA moiety linked to one molecule of ApoB(100). Recent data from large-scale prospective studies and genetic association studies provide highly suggestive evidence for a potentially causal role of Lp(a) in affecting risk of cardiovascular disease (CVD) in general populations. Patients with Type 2 diabetes display clustered metabolic abnormalities and elevated risk of CVD. Lower plasma Lp(a) levels were observed in diabetic patients in several recent studies. Epidemiology studies of Lp(a) and CVD risk in diabetic patients generated inconsistent results. We recently found that Lp(a)-related genetic markers did not predict CVD in two diabetic cohorts. The current data suggest that Lp(a) may differentially affect cardiovascular risk in diabetic patients and in the general population. More prospective studies, Mendelian randomization analysis and functional studies are needed to clarify the causal relationship of Lp(a) and CVD in diabetic patients.
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