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Low-Density Lipoprotein Cholesterol-Lowering Drugs: A Narrative Review.
Ferri, N, Ruscica, M, Fazio, S, Corsini, A
Journal of clinical medicine. 2024;(4)
Abstract
The modern history of cholesterol-lowering drugs started in 1972 when Dr. Akira Endo identified an active compound (compactin) that inhibited cholesterol biosynthesis from the culture broth of blue-green mold (Penicillium citrinum Pen-51). Since 1987, statins have represented the milestone for the treatment of atherosclerotic cardiovascular disease. A new therapy for the treatment of hypercholesterolemia since the discovery of statins is ezetimibe, the first and only agent inhibiting intestinal cholesterol absorption. Ezetimibe was approved by the FDA in October 2002. A year later, the association between gain-of-function PCSK9 genetic mutations and hypercholesterolemia was reported, and this discovery opened a new era in lipid-lowering therapies. Monoclonal antibodies and small-interfering RNA approaches to reduce PCSK9 were developed and approved for clinical use in 2015 and 2022, respectively. Finally, the newly approved bempedoic acid, an oral adenosine triphosphate citrate lyase inhibitor that lowers LDL-C, is able to reduce major adverse cardiovascular events in both primary and secondary prevention. In the present narrative review, we summarize the pharmacological properties and the clinical efficacy of all these agents currently used for a tailored therapy of hypercholesterolemia in patients with atherosclerotic cardiovascular disease.
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Prognostic Value of PCSK9 Levels in Premenopausal Women at Risk of Breast Cancer-Evidence from a 17-Year Follow-Up Study.
Ruscica, M, Macchi, C, Gandini, S, Macis, D, Guerrieri-Gonzaga, A, Aristarco, V, Serrano, D, Lazzeroni, M, Rizzuto, AS, Gaeta, A, et al
Cancers. 2024;(7)
Abstract
BACKGROUND AND AIM The involvement of cholesterol in cancer development remains a topic of debate, and its association with breast cancer has yet to be consistently demonstrated. Considering that circulating cholesterol levels depend on several concomitant processes, we tested the liability of plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in the context of breast neoplastic events. METHODS Within a prospective randomized breast cancer prevention trial we measured baseline plasma levels of PCSK9. A total of 235 at-risk premenopausal women were randomized and followed up for 17 years. Participants enrolled in this placebo-controlled, phase II, double-blind trial were randomly assigned to receive either tamoxifen 5 mg/d or fenretinide 200 mg/d, both agents, or placebo for 2 years. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models, adjusted for randomization strata (5-year Gail risk ≥ 1.3% vs. intraepithelial neoplasia or small invasive breast cancer of favorable prognosis), age, and treatment allocation. PCSK9 associations with biomarkers linked to breast cancer risk were assessed on blood samples collected at baseline. RESULTS The plasmatic PCSK9 median and interquartile range were 207 ng/mL and 170-252 ng/mL, respectively. Over a median follow-up period of 17 years and 89 breast neoplastic events, disease-free survival curves showed a hazard ratio of 1.002 (95% CI: 0.999-1.005, p = 0.22) for women with PCSK9 plasma levels ≥ 207 ng/mL compared to women with levels below 207 ng/mL. No differences between randomization strata were observed. We found a negative correlation between PCSK9 and estradiol (r = -0.305), maintained even after partial adjustment for BMI and age (r = -0.287). Cholesterol (r = 0.266), LDL-C (r = 0.207), non-HDL-C (r = 0.246), remnant cholesterol (r = 0.233), and triglycerides (r = 0.233) also correlated with PCSK9. CONCLUSIONS In premenopausal women at risk of early-stage breast cancer, PCSK9 did not appear to have a role as a prognostic biomarker of breast neoplastic events. Larger studies are warranted investigating patients in different settings.
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3.
Fixed Combination for the Treatment of Dyslipidaemia.
Ferri, N, Ruscica, M, Santos, RD, Corsini, A
Current atherosclerosis reports. 2023;(10):691-699
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Abstract
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.
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Proteomics and Lipidomics to unveil the contribution of PCSK9 beyond cholesterol lowering: a narrative review.
Gianazza, E, Macchi, C, Banfi, C, Ruscica, M
Frontiers in cardiovascular medicine. 2023;:1191303
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of the low-density lipoprotein receptor (LDLR), can play a direct role in atheroma development. Although advances in the understandings of genetic PCSK9 polymorphisms have enabled to reveal the role of PCSK9 in the complex pathophysiology of cardiovascular diseases (CVDs), increasing lines of evidence support non-cholesterol-related processes mediated by PCSK9. Owing to major improvements in mass spectrometry-based technologies, multimarker proteomic and lipidomic panels hold the promise to identify novel lipids and proteins potentially related to PCSK9. Within this context, this narrative review aims to provide an overview of the most significant proteomics and lipidomics studies related to PCSK9 effects beyond cholesterol lowering. These approaches have enabled to unveil non-common targets of PCSK9, potentially leading to the development of novel statistical models for CVD risk prediction. Finally, in the era of precision medicine, we have reported the impact of PCSK9 on extracellular vesicles (EVs) composition, an effect that could contribute to an increased prothrombotic status in CVD patients. The possibility to modulate EVs release and cargo could help counteract the development and progression of the atherosclerotic process.
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Nutraceutical approaches to non-alcoholic fatty liver disease (NAFLD): A position paper from the International Lipid Expert Panel (ILEP).
Rizzo, M, Colletti, A, Penson, PE, Katsiki, N, Mikhailidis, DP, Toth, PP, Gouni-Berthold, I, Mancini, J, Marais, D, Moriarty, P, et al
Pharmacological research. 2023;:106679
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Abstract
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.
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Updates in Small Interfering RNA for the Treatment of Dyslipidemias.
Carugo, S, Sirtori, CR, Gelpi, G, Corsini, A, Tokgozoglu, L, Ruscica, M
Current atherosclerosis reports. 2023;(11):805-817
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PURPOSE OF REVIEW Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders. RECENT FINDINGS The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.
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Omega-3 and cardiovascular prevention - Is this still a choice?
Ruscica, M, Sirtori, CR, Carugo, S, Calder, PC, Corsini, A
Pharmacological research. 2022;:106342
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Abstract
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.
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Effect of Bariatric Surgery on Flow-Mediated Vasodilation as a Measure of Endothelial Function: A Systematic Review and Meta-Analysis.
Jamialahmadi, T, Alidadi, M, Atkin, SL, Kroh, M, Almahmeed, W, Moallem, SA, Al-Rasadi, K, Rodriguez, JH, Santos, RD, Ruscica, M, et al
Journal of clinical medicine. 2022;(14)
Abstract
Objectives. Flow mediated vasodilation (FMD) is a marker of endothelial function and its decline is related to increased cardiovascular risk. This systematic review and meta-analysis evaluated the impact of bariatric surgery on FMD. Materials and methods. A systematic literature search in PubMed, Scopus, Embase, and Web of Science was performed to 1 May 2021. Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V2 software. All types of bariatric surgery were considered, with the inclusion that FMD had to have been tested before and after the surgical procedure. Meta-analysis was carried out using a random-effects model and the generic inverse variance approach. The leave-one-out approach was used for sensitivity analysis. To assess metabolic parameter confounders, a weighted random-effects meta-regression was used. Results. A meta-analysis and a systematic review of 23 studies (n = 891 individuals) demonstrated improvement in FMD following bariatric surgery (weighted mean difference (WMD): 5.867, 95% CI: 4.481, 7.252, p < 0.001; I2: 96.70). Iteratively removing each item in the meta-analysis did not result in a significant alteration in the pooled estimate of effect size. There was an improvement in FMD for up to 6 months following bariatric surgery in a meta-analysis from 7 trials that included 356 subjects (WMD: 5.248, 95% CI: 2.361, 8.135, p < 0.001; I2: 98.18). The meta-analysis from 9 trials (n = 414 subjects) showed an improvement in FMD 6 to 12 months after bariatric surgery (WMD: 5.451, 95% CI: 3.316, 7.587, p < 0.001; I2: 94.18). The meta-analysis from 10 trials (n = 414 subjects) demonstrated an improvement in FMD 12 months after bariatric surgery (WMD: 2.401, 95% CI: 0.944, 3.859, p = 0.001; I2: 88.35). Random-effects meta-regression did not show any association between the alteration in FMD and percent body mass index (BMI) change (slope: 0.0258; 95% CI: −0.323, 0.375; p = 0.884), or changes in blood pressure; however, there was an association between the changes in FMD and the duration of follow-up (slope: −0.106; 95% CI: −0.205, −0.008; p = 0.033) with greater changes in FMD after 12 months. Conclusions. Bariatric surgery significantly improved FMD that increased with time, and the resultant improvement in endothelial function was independent of weight loss or a reduction in blood pressure.
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Bempedoic Acid: for Whom and When.
Ruscica, M, Sirtori, CR, Carugo, S, Banach, M, Corsini, A
Current atherosclerosis reports. 2022;(10):791-801
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Abstract
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.
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The Role of High-Density Lipoprotein Cholesterol in 2022.
Sirtori, CR, Corsini, A, Ruscica, M
Current atherosclerosis reports. 2022;(5):365-377
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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.