Polygenic scores for cardiovascular risk factors improve estimation of clinical outcomes in CCB treatment compared to pharmacogenetic variants alone.

Pharmacogenetic variants are associated with clinical outcomes during Calcium Channel Blocker (CCB) treatment, yet whether the effects are modified by genetically predicted clinical risk factors is unknown. We analyzed 32,000 UK Biobank participants treated with dihydropiridine CCBs (mean 5.9 years), including 23 pharmacogenetic variants, and calculated polygenic scores for systolic and diastolic blood pressures, body fat mass, and other patient characteristics. Outcomes included treatment discontinuation and heart failure. Pharmacogenetic variant rs10898815-A (NUMA1) increased discontinuation rates, highest in those with high polygenic scores for fat mass. The RYR3 variant rs877087 T-allele alone modestly increased heart failure risks versus non-carriers (HR:1.13, p = 0.02); in patients with high polygenic scores for fat mass, lean mass, and lipoprotein A, risks were substantially elevated (HR:1.55, p = 4 × 10-5). Incorporating polygenic scores for adiposity and lipoprotein A may improve risk estimates of key clinical outcomes in CCB treatment such as treatment discontinuation and heart failure, compared to pharmacogenetic variants alone.

LP(a): Structure, Genetics, Associated Cardiovascular Risk, and Emerging Therapeutics.

Lipoprotein(a) [Lp(a)] is a molecule bound to apolipoprotein(a) with some similarity to low-density lipoprotein cholesterol (LDL-C), which has been found to be a risk factor for cardiovascular disease (CVD). Lp(a) appears to induce inflammation, atherogenesis, and thrombosis. Approximately 20% of the world's population has increased Lp(a) levels, determined predominantly by genetics. Current clinical practices for the management of dyslipidemia are ineffective in lowering Lp(a) levels. Evolving RNA-based therapeutics, such as the antisense oligonucleotide pelacarsen and small interfering RNA olpasiran, have shown promising results in reducing Lp(a) levels. Phase III pivotal cardiovascular outcome trials [Lp(a)HORIZON and OCEAN(a)] are ongoing to evaluate their efficacy in secondary prevention of major cardiovascular events in patients with elevated Lp(a). The future of cardiovascular residual risk reduction may transition to a personalized approach where further lowering of either LDL-C, triglycerides, or Lp(a) is selected after high-intensity statin therapy based on the individual risk profile and preferences of each patient.

Role of lipoprotein(a) in atherosclerotic cardiovascular disease: A review of current and emerging therapies.

Lipoprotein(a), or Lp(a), is structurally like low-density lipoprotein (LDL) but differs in that it contains glycoprotein apolipoprotein(a) [apo(a)]. Due to its prothrombotic and proinflammatory properties, Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. Lp(a) levels are genetically determined, and it is estimated that 20%-25% of the global population has an Lp(a) level ≥50 mg/dL (or ≥125 nmol/L). Diet and lifestyle interventions have little to no effect on Lp(a) levels. Lipoprotein apheresis is the only approved treatment for elevated Lp(a) but is time-intensive for the patient and only modestly effective. Pharmacological approaches to reduce Lp(a) levels and its associated risks are of significant interest; however, currently available lipid-lowering therapies have limited effectiveness in reducing Lp(a) levels. Although statins are first-line agents to reduce LDL cholesterol levels, they modestly increase Lp(a) levels and have not been shown to change Lp(a)-mediated ASCVD risk. Alirocumab, evolocumab, and inclisiran reduce Lp(a) levels by 20-25%, yet the clinical implications of this reduction for Lp(a)-mediated ASCVD risk are uncertain. Niacin also lowers Lp(a) levels; however, its effectiveness in mitigating Lp(a)-mediated ASCVD risk remains unclear, and its side effects have limited its utilization. Recommendations for when to screen and how to manage individuals with elevated Lp(a) vary widely between national and international guidelines and scientific statements. Three investigational compounds targeting Lp(a), including small interfering RNA (siRNA) agents (olpasiran, SLN360) and an antisense oligonucleotide (pelacarsen), are in various stages of development. These compounds block the translation of messenger RNA (mRNA) into apo(a), a key structural component of Lp(a), thereby substantially reducing Lp(a) synthesis in the liver. The purpose of this review is to describe current recommendations for screening and managing elevated Lp(a), describe the effects of currently available lipid-lowering therapies on Lp(a) levels, and provide insight into emerging therapies targeting Lp(a).

Impact of alirocumab/evolocumab on lipoprotein (a) concentrations in patients with familial hypercholesterolaemia: a systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Familial hypercholesterolaemia (FH) is a common hereditary genetic disorder, characterized by elevated circulating low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] concentrations, leading to atherosclerotic cardiovascular disease (ASCVD). Two types of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors- alirocumab and evolocumab- are efficient drugs in the treatment of FH, which can effectively reduce Lp(a) levels. MATERIAL AND METHODS: Embase, MEDLINE, and PubMed up to November 2022 were searched for randomized clinical trials (RCTs) evaluating the effect of alirocumab/evolocumab and placebo treatment on plasma Lp(a) levels in FH. Statistics were analysed by Review Manager (RevMan 5.3) and Stata 15.1. RESULTS: Eleven RCTs involved a total of 2408 participants. Alirocumab/evolocumab showed a significant efficacy in reducing Lp(a) [weighted mean difference (WMD): -20.10%, 95% confidence interval (CI): -25.59% to -14.61%] compared with placebo. In the drug type subgroup analyses, although the efficacy of evolocumab was slightly low (WMD: -19.98%, 95% CI: -25.23% to -14.73%), there was no difference with alirocumab (WMD: -20.54%, 95% CI: -30.07% to -11.02%). In the treatment duration subgroup analyses, the efficacy of the 12-week duration group (WMD: -17.61%, 95% CI: -23.84% to -11.38%) was lower than in the group of ≥ 24 weeks' duration (WMD: -22.81%, 95% CI: -31.56% to -14.07%). In the participants' characteristics subgroup analyses, the results showed that no differential effect of alirocumab/evolocumab therapy on plasma Lp(a) concentrations was observed (heterozygous FH [HeFH] WMD: -20.07%, 95% CI: -26.07% to -14.08%; homozygous FH [HoFH] WMD: -20.04%, 95% CI: -36.31% to -3.77%). Evaluation of all-cause adverse events (AEs) between alirocumab/evolocumab groups and placebo groups [relative risk (RR): 1.05, 95% CI: 0.98-1.12] implied no obvious difference between the 2 groups. CONCLUSIONS: Anti-PCSK9 drugs (alirocumab and evolocumab) may be effective as therapy for reducing serum Lp(a) levels in FH, and no differences were observed in treatment durations, participant characteristics, and other aspects of the 2 types of PCSk9 inhibitors. However, further experimental studies and RCTs are warranted to clarify the mechanism of PSCK9 inhibitors to lowering Lp(a) concentrations in FH.

Burden of lipoprotein(a) for patients with atherosclerotic cardiovascular disease: A retrospective analysis from the United States.

BACKGROUND: Lipoprotein(a) (Lp(a)) is an inherited, independent, and causal risk factor for atherosclerotic cardiovascular disease (ASCVD). OBJECTIVE: To assess the burden of elevated Lp(a) for patients with ASCVD in a real-world setting in the United States. METHODS: This retrospective cohort study assessed US patients with available Lp(a) measurement and established ASCVD using Optum's Clinformatics Data Mart database (2007-2020). Index date was defined as the first diagnosis of an ASCVD event. Patient demographics, medications, health care resource utilization (HCRU), and occurrence of cardiovascular events were assessed for patients with elevated (≥150 nmol/L) vs normal (≥65 nmol/L) Lp(a) levels, within the first year of index date. HCRU was characterized by inpatient hospitalization, inpatient length of stay (LOS), outpatient visits, and emergency department (ED) visits. All comparative analyses of patients with elevated (≥150 nmol/L) vs normal (≥65 nmol/L) Lp(a) levels within the first year of index date were adjusted for age, sex, baseline statin use, and diabetes. RESULTS: 8,372 patients with ASCVD and Lp(a) measurement in nmol/L were included in this study. Patient demographics and baseline clinical characteristics were similar among those with normal and elevated Lp(a). However, the proportion of patients receiving statins and ß-blockers at baseline were significantly higher in the elevated vs normal Lp(a) group (54.76% vs 42.91%, P < 0.0001, and 30.92% vs 27.32%, P = 0.0183, respectively). At 1 year of follow-up, the rates per 100 person-years for ASCVD-related inpatient hospitalizations, outpatient hospitalizations, and ED visits were higher among patients with elevated Lp(a) compared with normal Lp(a) (13.33 vs 9.46, 89.08 vs 85.10, and 2.89 vs 2.29, respectively). The mean LOS per ASCVD-related hospitalization was 7.21 days in the elevated and 6.26 days in the normal Lp(a) group (P = 0.3462). During the 1-year post-index follow-up period, 15% of patients in the elevated Lp(a) group required revascularization compared with 10% of patients in the normal Lp(a) group (P = 0.0002). The odds of composite myocardial infarction, ischemic stroke, and revascularization occurrence of events within the first year of index was significantly higher in the elevated Lp(a) group compared with the normal Lp(a) group (1.46; 95% CI = 1.20-1.77; P < 0.05). CONCLUSIONS: HCRU within the first year of ASCVD diagnosis is substantial among patients with ASCVD and elevated Lp(a). Relatively higher rates of inpatient hospitalizations, increased LOS per hospitalization, and requirement of revascularization procedures within the first year of ASCVD index diagnosis were observed in patients with elevated Lp(a) compared with normal Lp(a) levels. Lp(a) testing in routine clinical practice could help in identification of high-risk patients with ASCVD and play an important role in the overall cardiovascular risk management, aiming to reduce the HCRU associated with ASCVD. DISCLOSURES: Ms Fonseca, Dr Laguna, Dr Itani, Dr Rachel Studer, and Dr Ferber are employees of Novartis Pharma AG, Basel, Switzerland. Ms Byrne is an employee of Novartis AG, Dublin, Ireland. Dr Costa-Scharplatz is an employee of Novartis Sweden AB, Stockholm, Sweden. Dr Heo and Ms Dillon are employees of Genesis Research. Genesis Research was commissioned to conduct the study (data extraction and analysis) on behalf of Novartis Pharma AG.

Supporting evidence for lipoprotein(a) measurements in clinical practice.

High levels of lipoprotein(a) [Lp(a)] are causal for development of atherosclerotic cardiovascular disease and highly regulated by genetics. Levels are higher in Blacks compared to Whites, and in women compared to men. Lp(a)'s main protein components are apolipoprotein (apo) (a) and apoB100, the latter being the main component of Low-Density Lipoprotein (LDL) particles. Studies have identified Lp(a) to be associated with inflammatory, coagulation and wound healing pathways. Lack of validated and accepted assays to measure Lp(a), risk cutoff values, guidelines for diagnosis, and targeted therapies have added challenges to the field. Scientific efforts are ongoing to address these, including studies evaluating the cardiovascular benefits of decreasing Lp(a) levels with targeted apo(a) lowering treatments. This review will provide a synopsis of evidence-based effects of high Lp(a) on disease presentation, highlight available guidelines and discuss promising therapies in development. We will conclude with current clinical information and future research needs in the field.

Potential of Lipoprotein(a)-Lowering Strategies in Treating Coronary Artery Disease.

High levels of lipoprotein(a) [Lp(a)] are considered causal risk factor of cardiovascular disease (CVD), including aortic stenosis. The 2019 ESC/EAC guidelines for the management of dyslipidaemias recommend to measure Lp(a) at least once in each adult person's lifetime to identify those with inherited Lp(a) levels > 180 mg/dL (> 430 nmol/L) who may have a cardiovascular risk similar to heterozygous familial hypercholesterolaemia or in selected patients with a family history of premature CVD and for reclassification in people who are borderline between moderate- and high-risk. Some lipid-lowering agents not specific for Lp(a) have shown to reduce Lp(a) levels (niacin, PCSK9 inhibitors and CETP inhibitors). Prespecified analyses from the FOURIER trial have shown that participants who had reduction in Lp(a) levels with PCSK9 levels had a decreased risk of cardiovascular events. To lower Lp(a), two antisense oligonucleotides are under development targeting apolipoprotein B and apolipoprotein (a). Mipomersen is an oligonucleotide that targets apolipoprotein B, with a potential benefit in reducing Lp(a) by 20-50%. AKCEA-APO(a)-LRX is another antisense oligonucleotide targeting Lp(a) and reducing Lp(a) by 50-80%. A Phase III study with AKCEA-APO(a)-LRX will start in order to evaluate the effect on cardiovascular outcomes.

Abnormalities of triglyceride rich lipoproteins (TRLs) in type 2 diabetes and insulin resistance

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Lipoprotein[a] and cancer: anti-neoplastic effect besides its cardiovascular potency.

While the death rate from cancer has substantially decreased over the past decade, the search for effective and tolerable therapies is a great challenge as yet. The evidence that malignant cells cannot grow to a clinically detectable tumor mass and spread in the absence of an adequate vascular support, has opened a new area of research towards the selective inhibition or even destruction of tumor vessels. Angiostatin and angiostatin-related proteins are a family of specific angiogenesis inhibitors produced by tumors from a family of naturally occurring proteins, which also includes plasminogen and lipoprotein[a]. The anti-angiogenic activity of these proteins resides in cryptic and highly-repetitive molecular domains hidden within the protein moiety, called kringles. Lipoprotein[a] is an intriguing molecule consisting of a low-density lipoprotein core in addition to the covalently bound apolipoprotein[a]. Apolipoprotein[a] is characterized by an inactive protease domain, a single copy of the plasminogen kringle V and multiple repeats of domains homologous to the plasminogen kringle IV. Reliable studies on animal models indicate that the proteolytic break-down products of apolipoprotein[a] would posses anti-angiogenic and anti-tumoral properties both in vitro and in vivo, a premise to develop novel therapeutic modalities which may efficiently suppress tumor growth and metastasis. This review is focused on the biochemical structure, metabolism and the anti-angiogenic activity of this unique and elusive kringle-containing lipoprotein.