Lipid-lowering approaches to manage statin-intolerant patients.

Statins have improved the potential to prevent cardiovascular disease events and to prolong the lives of patients. Statins, among the most widely used drugs worldwide, reduce the levels of low-density lipoprotein cholesterol (LDL-C) by an average of 30-50%. However, non-adherence to statin therapy, due to statin intolerance, might be as high as 60% after 24 months of treatment and is associated with a 70% increase in the risk of cardiovascular disease events. Statin intolerance can be classified as a complete inability to tolerate any dose of a statin or a partial intolerance with the inability to tolerate the dose necessary to achieve the patient-specific therapeutic objective. Reasons for discontinuation are many, with statin-associated muscle symptoms being cited as the most frequent reason for stopping therapy and the incidence of muscle symptoms increasing with treatment intensity. Considering the causal effect of LDL-C in the atherosclerotic process, clinicians should consider that regardless of the lipid-lowering drugs patients are willing to take, any reduction in LDL-C they achieve will afford them some benefit in reducing cardiovascular risk. Besides statins, the current therapeutic armamentarium offers different strategies to reach LDL-C targets in statin-intolerant patients (i.e. a fixed combination between a lower dose of statin plus ezetimibe, bempedoic acid, or proprotein convertase subtilisin/kexin type 9 inhibition).

Circulating PCSK9 as a prognostic biomarker of cardiovascular events in individuals with type 2 diabetes: evidence from a 16.8-year follow-up study.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality, being twofold to fourfold more common in patients with type 2 diabetes mellitus (T2DM) than in individuals without diabetes. However, despite this decade-old knowledge, the identification of a specific prognostic risk biomarker remains particularly challenging. METHODS: Taking advantage of a large sample of Caucasian patients (n = 529) with a diagnosis of T2DM followed for a median of 16.8 years, the present study was aimed at testing the hypothesis that fasting serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels could be prognostic for major adverse cardiovascular events (MACE) and all-cause mortality. RESULTS: Median levels of PCSK9 were 259.8 ng/mL, being higher in women compared to men and increasing even more in the presence of a complication (e.g., diabetic kidney disease). PCSK9 positively correlated with markers of blood glucose homeostasis (e.g., HbA1c, fasting insulin and HOMA-IR) and the atherogenic lipid profile (e.g., non-HDL-C, apoB and remnant cholesterol). Serum PCSK9 predicted new-onset of MACE, either fatal or non-fatal, only in women (Odds Ratio: 2.26, 95% CI 1.12-4.58) and all-cause mortality only in men (Hazard Ratio: 1.79, 95% CI 1.13-2.82). CONCLUSIONS: Considering that up to two-thirds of individuals with T2DM develop ASCVD in their lifetime, the assessment of circulating PCSK9 levels can be envisioned within the context of a biomarker-based strategy of risk stratification. However, the sex difference found highlights an urgent need to develop sex-specific risk assessment strategies. TRIAL REGISTRATION: It is a retrospective study.

Fixed Combination for the Treatment of Dyslipidaemia.

PURPOSE OF REVIEW: It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid guideline-recommended targets. Thus, fixed-dose combinations of statins/ezetimibe, bempedoic acid/ezetimibe and statins/fibrates may represent a further armamentarium in the field of lipid-lowering approaches in these individuals. RECENT FINDINGS: The combination therapy of moderate-intensity statin with ezetimibe is not inferior to high-intensity statin monotherapy in reducing cardiovascular outcomes. Drug discontinuation or dose reduction is inferior with fixed-dose combination. The fixed-dose combination of bempedoic acid with ezetimibe is superior to bempedoic acid in monotherapy in lowering LDL-C and in reducing high-sensitivity C-reactive protein concentrations. The combination fenofibrate with atorvastatin is superior to monotherapies in lowering triglycerides. Lipid-lowering fixed-dose combinations may guarantee a higher therapy adherence, representing a better approach to control plasma lipids and thus ameliorate ASCVD burden. Additional studies will define the advantages on cardiovascular outcomes in high and very high-risk patients.

Nutraceutical approaches to non-alcoholic fatty liver disease (NAFLD): A position paper from the International Lipid Expert Panel (ILEP).

Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety.

Hypocholesterolaemic treatment in coronary unit: from statins to anti PCSK9 therapies and bempedoic acid.

The knowledge that roughly 20% of survivors from an acute coronary syndrome (ACS) event experience a subsequent ischaemic cardiovascular event within 24 months with a 5-year mortality range between 19 and 22% highlights the importance of the lipid-lowering strategies in the secondary prevention after ACS. In this framework, statin treatment significantly improves clinical outcome after ACS. Within this remit, in the present review we critically discuss the use of statin and non-statin lipid-lowering approaches (ezetimibe, evolocumab, alirocumab, inclisiran, and bempedoic acid) in the early management of ACS patients. Relative to this latter aspect, the knowledge that circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels are raised during ACS could be a generating hypothesis justifying the use of PCSK9 inhibitors in ACS. Thus, in a field fraught of uncertainty, the main barrier to the widespread prescription of non-statin agents (e.g. PCSK9 inhibitors) relates to their costs when compared with other lipid-lowering agents (e.g. statins and ezetimibe).

Proprotein Convertase Subtilisin/Kexin Type 9: A View beyond the Canonical Cholesterol-Lowering Impact.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), mainly synthetized and released by the liver, represents one of the key regulators of low-density lipoprotein cholesterol. Although genetic and interventional studies have demonstrated that lowering PCSK9 levels corresponds to a cardiovascular benefit, identification of non-cholesterol-related processes has emerged since its discovery. Besides liver, PCSK9 is also expressed in many tissues (eg, intestine, endocrine pancreas, and brain). The aim of the present review is to describe and discuss PCSK9 pathophysiology and possible non-lipid-lowering effects whether already extensively characterized (eg, inflammatory burden of atherosclerosis, triglyceride-rich lipoprotein metabolism, and platelet activation), or to be unraveled (eg, in adipose tissue). The identification of novel transcriptional factors in the promoter region of human PCSK9 (eg, ChREBP) characterizes new mechanisms explaining how controlling intrahepatic glucose may be a therapeutic strategy to reduce cardiovascular risk in type 2 diabetes. Finally, the evidence describing PCSK9 as involved in cell proliferation and apoptosis raises the possibility of this protein being involved in cancer risk.

The Role of High-Density Lipoprotein Cholesterol in 2022.

PURPOSE OF THE REVIEW: High-density lipoproteins (HDL) are responsible for the transport in plasma of a large fraction of circulating lipids, in part from tissue mobilization. The evaluation of HDL-associated cholesterol (HDL-C) has provided a standard method for assessing cardiovascular (CV) risk, as supported by many contributions on the mechanism of this arterial benefit. The present review article will attempt to investigate novel findings on the role and mechanism of HDL in CV risk determination. RECENT FINDINGS: The most recent research has been aimed to the understanding of how a raised functional capacity of HDL, rather than elevated levels per se, may be responsible for the postulated CV protection. Markedly elevated HDL-C levels appear instead to be associated to a raised coronary risk, indicative of a U-shaped relationship. While HDL-C reduction is definitely related to a raised CV risk, HDL-C elevations may be linked to non-vascular diseases, such as age-related macular disease. The description of anti-inflammatory, anti-oxidative and anti-infectious properties has indicated potential newer areas for diagnostic and therapeutic approaches. In the last two decades inconclusive data have arisen from clinical trials attempting to increase HDL-C pharmacologically or by way of recombinant protein infusions (most frequently with the mutant A-I Milano); prevention of stent occlusion or heart failure treatment have shown instead significant promise. Targeted clinical studies are still ongoing.

PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

PURPOSE OF REVIEW: Since the clinical benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors occurs in a setting of reducing low-density lipoprotein-cholesterol (LDL-C) to unprecedentedly low levels, it becomes of interest to investigate possible adverse effects pertaining to the risk of new-onset diabetes (NOD). RECENT FINDINGS: While safety results reported in either meta-analyses or cardiovascular outcome trials FOURIER (with evolocumab) and ODYSSEY (with alirocumab) did not rise the incidence of NOD, Mendelian randomization analyses were almost concordant in showing an increased risk of NOD. This evidence was in line with post-marketing safety reports highlighting that evolocumab and alirocumab were primarily related to mild hyperglycaemia rather than diabetes, with most of the hyperglycaemic events occurring during the first 6 months of treatment. Considering the different nature of genetic studies and of randomized controlled trials, with careful monitoring of patients, particularly in the earlier phases of treatment, and the identification of those more susceptible to develop NOD, treatment with PCSK9 inhibitors should be of minimal concern.

Bempedoic Acid: for Whom and When.

PURPOSE OF REVIEW: The aim of creating an orally active non-statin cholesterol-lowering drug was achieved with bempedoic acid, a small linear molecule providing both a significant low-density lipoprotein cholesterol (LDL-C) reduction and an anti-inflammatory effect by decreasing high-sensitivity C-reactive protein. Bempedoic acid antagonizes ATP citrate-lyase, a cytosolic enzyme upstream of HMGCoA reductase which is the rate-limiting step of cholesterol biosynthesis. Bempedoic acid is a pro-drug converted to its active metabolite by very-long-chain acyl-CoA synthetase 1 which is present mostly in the liver and absent in skeletal muscles. This limits the risk of myalgia and myopathy. The remit of this review is to give clinical insights on the safety and efficacy of bempedoic acid and to understand for whom it should be prescribed. RECENT FINDINGS: Bempedoic acid with a single daily dose (180 mg) reduces LDL-C by a mean 24.5% when given alone, by 18% when given on top of a major statin and by 38-40% when given in a fixed-dose combination with ezetimibe. Bempedoic acid does not lead to the risk of new-onset diabetes, and moderately improves the glycaemic profile. The extensive knowledge on bempedoic acid mechanism, metabolism and side effects has led to an improved understanding of the potential benefits of this agent and offers a possible alternative to cardiologists and clinical practitioners somewhat worn out today by the occurrence of the muscular side effects of statins.

Omega-3 and cardiovascular prevention - Is this still a choice?

There is currently growing attention being paid to the role of elevated triglycerides (TGs) as important mediators of residual atherosclerotic cardiovascular disease (ASCVD) risk. This role is supported by genetic studies and by the persistent residual risk of ASCVD, even after intensive statin therapy. Although TG lowering drugs have shown conflicting results when tested in cardiovascular outcome trials, data from the REDUCE-IT study with the ethyl ester of ω-3 eicosapentaenoic acid (EPA) have revived hope in this area of research. The aim of the present review is to critically discuss the most recent large trials with ω-3 fatty acids (FAs) trying to elucidate mechanistic and trial-related differences, as in the case of REDUCE-IT and STRENGTH studies. The ω-3 FAs may lower cardiovascular risk through a number of pleiotropic mechanisms, e.g., by lowering blood pressure, by mediating antithrombotic effects, by providing precursors for the synthesis of specialized proresolving mediators that can inhibit inflammation or by modulating the lipid rafts enriched in cholesterol and sphingolipids. In conclusion, in a field fraught with uncertainties, the ω-3 FAs and especially high dose icosapent ethyl (the ethyl ester of EPA) are at present a most valuable therapeutic option to reduce the ASCVD risk.

Pharmacological rationale for the very early treatment of acute coronary syndrome with monoclonal antibodies anti-PCSK9.

Immediate and aggressive lipid lowering therapies after acute coronary syndromes (ACS) and percutaneous coronary interventions (PCI) are supported by the ESC/EAS dyslipidemia guidelines, recommending the initiation of high-intensity statin therapy within the first 1-4 days of hospitalization. However, whether non statin lipid-lowering agents, added to statin treatment, could produce a further reduction in the risk of major adverse cardiovascular events (MACE) is still unknown. Thus, the efficacy of early treatment post-ACS with monoclonal antibodies (mAbs) anti PCSK9, evolocumab and alirocumab, is under investigation. The rationale to explore the rapid and aggressive pharmacological intervention with PCSK9 mAbs is supported by at least five confirmatory data in ACS: 1) circulating PCSK9 levels are raised during ACS 2) PCSK9 may stimulate platelet reactivity, this last being pivotal in the recurrence of ischemic events; 3) PCSK9 is associated with intraplaque inflammation, macrophage activation and endothelial dysfunction; 4) PCSK9 concentrations are associated with inflammation in the acute phase of ACS; and 5) statins raise PCSK9 levels promptly and, at times, dramatically. In this scenario, appropriate pharmacodynamic characteristics of anti PCSK9 therapies are a prerequisite for an effective response. Monoclonal antibodies act on circulating PCSK9 with a direct and rapid binding by blocking the interaction with the low-density lipoprotein receptor (LDLR). Evolocumab and alirocumab show a very rapid (within 4 h) and effective suppression of circulating unbound PCSK9 (- 95 % ÷ - 97 %). This inhibition results in a significant reduction of LDL-cholesterol (LDL-C) after 48 h (- 35 %) post injection with a full effect after 7-10 days (55-75 %). The complete and swift inhibitory action by evolocumab and alirocumab could have a potential clinical impact in ACS patients, also considering their potential inhibition of PCSK9 within the atherosclerotic plaque. Thus, administration of evolocumab or alirocumab is effective in lowering LDL-C levels in ACS, although the efficacy to prevent further cardiovascular (CV) events is still undetermined. The answer to this question will be provided by the ongoing clinical trials with evolocumab and alirocumab in ACS. In the present review we will discuss the pharmacological and biological rationale supporting the potential use of PCSK9 mAbs in ACS patients and the emerging evidence of evolocumab and alirocumab treatment in this clinical setting.

Role of lipoprotein(a) in plaque progression.

Identified by Berg in 1963, lipoprotein(a) represents a key contemporary residual risk pathway in atherosclerotic cardiovascular disease (ASCVD) secondary prevention. Indeed, epidemiological and genetic studies have undoubtedly demonstrated that lipoprotein(a) is one of the strongest causal risk factors of ASCVD. Although a risk threshold has been set between 30 and 50 mg/dL, depending on the ethnicity, a linear risk gradient across the distribution has been demonstrated. In the context of the atherosclerotic process, hyperlipoproteinaemia(a) contributes to the atherosclerotic plaque formation by deposition of cholesterol in the same manner as low-density lipoprotein (LDL) cholesterol, due to the LDL particle component of lipoprotein(a). Lipoprotein(a) accumulates in human coronary and carotid atherosclerotic lesions. High concentrations of lipoprotein(a) are associated with accelerated progression of the necrotic core, but not with coronary calcium score (CAC), although in the latter case, the evaluation of lipoprotein(a) can overcome the potential limitation of CAC to capture the totality of ASCVD risk in asymptomatic individuals. Finally, in the absence of a pharmacological approach to lower lipoprotein(a) to the extent required to achieve a cardiovascular benefit, implementation strategies that increase awareness among the population, patients, and healthcare providers on the importance of lipoprotein(a) in the development of ASCVD are eagerly needed.

Impact of Atorvastatin on Skeletal Muscle Mitochondrial Activity, Locomotion and Axonal Excitability-Evidence from ApoE-/- Mice.

The cardiovascular benefit of statins is well established. However, only 20% of high-risk patients remain adequately adherent after 5 years of treatment. Among reasons for discontinuation, statin associated-muscle pain symptoms are the most prevalent. Aim of the present study was to evaluate the impact of high dose atorvastatin on skeletal muscle mitochondrial activity, aerobic and anaerobic exercise, and axonal excitability in a murine model of atherosclerosis. ApoE-/- mice were fed 12 weeks a high-fat high-cholesterol diet alone or containing atorvastatin (40 mg/Kg/day). Outcomes were the evaluation of muscle mitochondrial functionality, locomotion, grip test, and axonal excitability (compound action potential recording analysis of Aα motor propioceptive, Aß mechanoceptive and C nociceptive fibres). Atorvastatin led to a reduction in muscle mitochondrial biogenesis and mitochondrial ATP production. It did not affect muscular strength but led to a time-dependent motor impairment. Atorvastatin altered the responsiveness of mechanoceptive and nociceptive fibres, respectively, the Aß and C fibres. These findings point out to a mild sensitization on mechanical, tactile and pain sensitivity. In conclusion, although the prevalence of muscular side effects from statins may be overestimated, understanding of the underlying mechanisms can help improve the therapeutic approach and reassure adherence in patients needing-to-be-treated.

PCSK9 Confers Inflammatory Properties to Extracellular Vesicles Released by Vascular Smooth Muscle Cells.

Vascular smooth muscle cells (VSMCs) are key participants in both early- and late-stage atherosclerosis and influence neighbouring cells possibly by means of bioactive molecules, some of which are packed into extracellular vesicles (EVs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed and secreted by VSMCs. This study aimed to unravel the role of PCSK9 on VSMCs-derived EVs in terms of content and functionality. EVs were isolated from human VSMCs overexpressing human PCSK9 (VSMCPCSK9-EVs) and tested on endothelial cells, monocytes, macrophages and in a model of zebrafish embryos. Compared to EVs released from wild-type VSMCs, VSMCPCSK9-EVs caused a rise in the expression of adhesion molecules in endothelial cells and of pro-inflammatory cytokines in monocytes. These acquired an increased migratory capacity, a reduced oxidative phosphorylation and secreted proteins involved in immune response and immune effector processes. Concerning macrophages, VSMCPCSK9-EVs enhanced inflammatory milieu and uptake of oxidized low-density lipoproteins, whereas the migratory capacity was reduced. When injected into zebrafish embryos, VSMCPCSK9-EVs favoured the recruitment of macrophages toward the site of injection. The results of the present study provide evidence that PCSK9 plays an inflammatory role by means of EVs, at least by those derived from smooth muscle cells of vascular origin.

Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9: The Role of STAT3.

In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokine levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of STAT3. In HepG2 cells, leptin and resistin up-regulated PCSK9 gene and protein expression, as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knockdown of STAT3 did not affect the expression of leptin and resistin receptors or that of PCSK9. The analysis of the human PCSK9 promoter region showed that the two adipokines raised PCSK9 promoter activity via the involvement of a sterol regulatory element motif. In healthy males, a positive association between circulating leptin and PCSK9 levels was found only when the body mass index was <25 kg/m2. In conclusion, this study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9.

Nonalcoholic fatty liver disease or metabolic dysfunction-associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches.

BACKGROUND: A consensus of experts has proposed to replace the term nonalcoholic fatty liver disease (NAFLD), whose global prevalence is 25%, with metabolic dysfunction-associated fatty liver disease (MAFLD), to describe more appropriately the liver disease related to metabolic derangements. MAFLD is closely intertwined with type 2 diabetes, obesity, dyslipidaemia, all linked to a rise in the risk of cardiovascular disease (CVDs). Since controversy still stands on whether or not NAFLD/MAFLD raises the odds of CVD, the present review aims to evaluate the impact of NAFLD/MAFLD aetiologies on CV health and the potential correction by dietary and drug approaches. RESULTS: Epidemiological studies indicate that NAFLD raises risk of fatal or non-fatal CVD events. NAFLD patients have a higher prevalence of arterial plaques and stiffness, coronary calcification, and endothelial dysfunction. Although genetic and environmental factors strongly contribute to NAFLD pathogenesis, a Mendelian randomization analysis indicated that the PNPLA3 genetic variant leading to NAFLD may not be causally associated with CVD risk. Among other genetic variants related to NAFLD, TM6SF2 appears to be protective, whereas MBOAT7 may favour venous thromboembolism. CONCLUSIONS: NAFLD is correlated to a higher CVD risk which may be ameliorated by dietary interventions. This is not surprising, since new criteria defining MAFLD include other metabolic risk abnormalities fuelling development of serious adverse extrahepatic outcomes, for example CVD. The present lack of a targeted pharmacological approach makes the identification of patients with liver disease at higher CVD risk (eg diabetes, hypertension, obesity or high levels of C-reactive protein) of major clinical interest.

Prognostic parameters of in-hospital mortality in COVID-19 patients-An Italian experience.

Background During COVID-19 outbreak, Italy was the first country in Europe to be heavily affected with an intensive care unit mortality of 26%. In order to reduce this percentage, physicians should establish clear and objective criteria to stratify COVID-19 patients at high risk of in-hospital death. Thus, the aim has been to test a large spectrum of variables ranging from clinical evaluation to laboratory biomarkers to identify which parameter would best predict all-cause in-hospital mortality in COVID-19 patients. Design observational study. Results Multivariate Cox regression analysis showed that each 5 years of increase in age corresponded to a hazard ratio (HR) of 1.28 (95% CI 1.00-1.65, P = .050); each increment of 803 ng/L of N-terminal pro-B-type natriuretic peptide (NT-proBNP) corresponded to a HR of 1.24 (95% CI 1.11-1.39, P < .001); each increment of 58 ng/L of interleukin (IL)-6 corresponded to a HR of 1.23 (95% CI 1.09-1.40, P < .001), and each increment of 250 U/L of lactate dehydrogenase (LDH) corresponded to a HR of 1.23 (95% CI 1.10-1.37, P < .001). According to the calculated cut-points for age (≥70 years), NT-proBNP (≥803 ng/L), IL-6 (≥58 ng/L) and LDH (≥371 U/L) when 2 out of these 4 were overcome, the HR was 2.96 (95% CI 1.97-4.45, P < .001). Conclusion In COVID-19 patients, besides age, the evaluation of three biochemical parameters, available in few hours after hospital admission can predict in-hospital mortality regardless of other comorbidities.

Cardiovascular risk and testosterone - from subclinical atherosclerosis to lipoprotein function to heart failure.

The cardiovascular (CV) benefit and safety of treating low testosterone conditions is a matter of debate. Although testosterone deficiency has been linked to a rise in major adverse CV events, most of the studies on testosterone replacement therapy were not designed to assess CV risk and thus excluded men with advanced heart failure or recent history of myocardial infarction or stroke. Besides considering observational, interventional and prospective studies, this review article evaluates the impact of testosterone on atherosclerosis process, including lipoprotein functionality, progression of carotid intima media thickness, inflammation, coagulation and thromboembolism, quantification of plaque volume and vascular calcification. Until adequately powered studies evaluating testosterone effects in hypogonadal men at increased CV risk are available (TRAVERSE trial), clinicians should ponder the use of testosterone in men with atherosclerotic cardiovascular disease and discuss benefit and harms with the patients.

Lipid Lowering Drugs: Present Status and Future Developments.

PURPOSE OF REVIEW: Based on the recent data of the DA VINCI study, it is clear that, besides utilization of statins, there is a need to increase non-statin lipid lowering approaches to reduce the cardiovascular burden in patients at highest risk. RECENT FINDINGS: For hypercholesterolemia, the small synthetic molecule bempedoic acid has the added benefit of selective liver activation, whereas inclisiran, a hepatic inhibitor of the PCSK9 synthesis, has comparable effects with PCSK9 monoclonal antibodies. For hypertriglyceridemia, cardiovascular benefit has been achieved by the use of icosapent ethyl, whereas results with pemafibrate, a selective agonist of PPAR-α, are eagerly awaited. In the era of RNA-based therapies, new options are offered to dramatically reduce levels of lipoprotein(a) (APO(a)LRX) and of triglycerides (ANGPTL3LRX and APOCIII-LRx). Despite the demonstrated benefits of statins, a large number of patients still remain at significant risk because of inadequate LDL-C reduction or elevated blood triglyceride-rich lipoproteins or lipoprotein(a). The area of lipid modulating agents is still ripe with ideas and major novelties are to be awaited in the next few years.

Lipoprotein(a): Knowns, unknowns and uncertainties.

Over the last 10 years, there have been advances on several aspects of lipoprotein(a) which are reviewed in the present article. Since the standard immunoassays for measuring lipoprotein(a) are not fully apo(a) isoform-insensitive, the application of an LC-MS/MS method for assaying molar concentrations of lipoprotein(a) has been advocated. Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) as a causal risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, the relative importance of molar concentration, apo(a) isoform size or variants within the LPA gene is still controversial. Lipoprotein(a)-raising single nucleotide polymorphisms has not been shown to add on value in predicting ASCVD beyond lipoprotein(a) concentrations. Although hyperlipoproteinemia(a) represents an important confounder in the diagnosis of familial hypercholesterolemia (FH), it enhances the risk of ASCVD in these patients. Thus, identification of new cases of hyperlipoproteinemia(a) during cascade testing can increase the identification of high-risk individuals. However, it remains unclear whether FH itself increases lipoprotein(a). The ASCVD risk associated with lipoprotein(a) seems to follow a linear gradient across the distribution, regardless of racial subgroups and other risk factors. The inverse association with the risk of developing type 2 diabetes needs consideration as effective lipoprotein(a) lowering therapies are progressing towards the market. Considering that Mendelian randomization analyses have identified the degree of lipoprotein(a)-lowering that is required to achieve ASCVD benefit, the findings of the ongoing outcome trial with pelacarsen will clarify whether dramatically lowering lipoprotein(a) levels can reduce the risk of ASCVD.