Reduction In Low-density Lipoprotein Cholesterol Levels Research Articles

Inclisiran: the preclinical discovery and development of a novel therapy for the treatment of atherosclerosis

ABSTRACT Introduction Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of global morbidity and mortality. Lipid lowering therapy (LLT) constitutes the cornerstone of ASCVD prevention and treatment. However, several patients fail to achieve therapeutic goals due to low treatment adherence or limitations of standard-of-care (SoC) LLTs. Inclisiran represents a pivotal low-density lipoprotein cholesterol (LDL-C) lowering agent aiming to address current unmet needs in LLT. It is the first available small interfering RNA (siRNA) LLT, specifically targeting PCSK9 mRNA and leading to post-transcriptional gene silencing (PTGS) of the PCSK9 gene. Areas covered Promising phase III trials revealed an ~ 50% reduction in LDL-C levels with subcutaneous inclisiran administration on days 1 and 90, followed by semiannual booster shots. Coupled with inclisiran’s favorable safety profile, these findings led to its approval by both the EMA and FDA. Herein, the authors highlight the preclinical discovery and development of this agent and provide the reader with their expert perspectives. Expert opinion The evolution of gene-silencing treatments offers new perspectives in therapeutics. Inclisiran appears to have the potential to revolutionize ASCVD prevention and treatment, benefiting millions of patients. Ensuring widespread availability of Inclisiran, as well as managing additional healthcare costs that may arise, should be of paramount importance.

Activation of lipophagy ameliorates cadmium-induced neural tube defects via reducing low density lipoprotein cholesterol levels in mouse placentas

Neural tube defects (NTDs) represent a prevalent and severe category of congenital anomalies in humans. Cadmium (Cd) is an environmental teratogen known to cause fetal NTDs. However, its underlying mechanisms remain elusive. This study aims to investigate the therapeutic potential of lipophagy in the treatment of NTDs, providing valuable insights for future strategies targeting lipophagy activation as a means to mitigate NTDs.We successfully modeled NTDs by Cd exposure during pregnancy. RNA sequencing was employed to investigate the transcriptomic alterations and functional enrichment of differentially expressed genes in NTD placental tissues. Subsequently, pharmacological/genetic (Atg5-/- placentas) experiments confirmed that inducing placental lipophagy can alleviate Cd induced-NTDs. We found that Cd exposure caused NTDs. Further analyzed transcriptomic data from the placentas with NTDs which revealed significant downregulation of low-density lipoprotein receptor associated protein 1(Lrp1) gene expression responsible for positive regulation of low-density lipoprotein cholesterol (LDL-C) transport. Correspondingly, there was an increase in maternal serum/placenta/amniotic fluid LDL-C content. Subsequently, we have discovered that Cd exposure activated placental lipophagy. Pharmacological/genetic (Atg5-/- placentas) experiments confirmed that inducing placental lipophagy can alleviate Cd induced-NTDs. Furthermore, our findings demonstrate that activation of placental lipophagy effectively counteracts the Cd-induced elevation in LDL-C levels. Lipophagy serves to mitigate Cd-induced NTDs by reducing LDL-C levels within mouse placentas.

Metformin-Induced Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition Further Decreases Low-Density Lipoprotein Cholesterol Following Statin Treatment in Patients With Coronary Artery Disease and Without Diabetes.

In vitro investigations have established metformin's capacity to downregulate proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, suggesting a potential beneficial effect on atherogenic lipoprotein particles when combined with metformin therapy. Our objective was to assess whether metformin could mitigate statin-induced adverse effects on PCSK9, thereby improving lipid profiles in patients with coronary artery disease (CAD) but without diabetes. Employing an open-label, placebo-controlled, randomized trial, we randomized patients with CAD but without diabetes into CLA (cholesterol-lowering agents alone: atorvastatin±ezetimibe, n = 38) and Met + CLA groups (metformin plus CLA, n = 33) in a 1:1 ratio. The primary end point was the therapeutic impact of 1-month metformin combination treatment on low-density lipoprotein cholesterol (LDL-C) and PCSK9 levels. Baseline LDL-C and PCSK9 levels were 76.18 mg·dL -1 and 80.54 ng·mL -1 , respectively. After 1 month, metformin significantly reduced LDL-C (-20.81%, P < 0.001), enabling 72% of patients to attain guideline-recommended LDL-C goals. Noteworthy reductions in PCSK9 levels (-15.03%, P < 0.001) were observed. Moreover, Met + CLA markedly reduced LDL particle number more than CLA alone (-10.65% vs. 1.45%, P = 0.009), primarily due to diminished small-dense LDL particle count. Mechanistically, our study demonstrated metformin's inhibition of statin-induced PCSK9 expression in human hepatocellular cells. In summary, a 1-month metformin combination regimen reduced LDL-C levels in patients with CAD but without diabetes by inhibiting PCSK9 expression. Chinese Clinical Trial Registry identifier: ChiCTR1900026925 (26/10/2019).

Impact of Lipoprotein(a) Levels on Cardiovascular Risk Estimation.

A new cardiovascular risk (CVR) calculator that incorporates Lipoprotein(a) [Lp(a)] levels has recently been designed. To estimate CVR using the new score and to identify the reduction in low-density lipoprotein cholesterol (LDL-C) or systolic blood pressure (SBP) necessary to balance the risk attributable to Lp(a). CVR throughout life and at 10 years was estimated with the new score in patients in primary prevention, both considering and not considering the value of Lp(a). When the estimated risk considering Lp(a) levels exceeded the baseline risk, the reduction in LDL-C levels or SBP necessary to balance the risk attributable to Lp(a) was calculated. In total, 671 patients (mean age 54.2 years, 47.2% women) were included. Globally, 22.7% of the population had high Lp(a) values (>50 mg/dL or >125 nmol/L). When calculating CVR throughout life and considering the Lp(a) value, the global risk increased in 66.7% of cases (median 19.3%). Similar results were observed when we assessed the 10-year risk. The risk associated with Lp(a) could be completely compensated by decreasing LDL-C (average 21 mg/dL) or SBP (average 6.3 mmHg) in 79.2% and 74.7% of cases, respectively. When calculating the CVR with the new score, two-thirds and one-third of the population were bidirectionally recategorized as 'up' or 'down,' respectively. The decrease in LDL-C or SBP mitigated the increased risk caused by Lp(a) levels across a substantial proportion of patients.

Combined hypolipidemic therapy with rosuvastatin and ezetimibe is the key to success in the treatment and prevention of cardiovascular diseases

Combined hypolipidemic therapy with rosuvastatin and ezetimibe is the key to success in the treatment and prevention of cardiovascular diseases

Consensus document on diagnosis and management of familial hypercholesterolemia from the Italian Society for the Study of Atherosclerosis (SISA)

AimsFamilial Hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism that causes an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Although early diagnosis and treatment of FH can significantly improve the cardiovascular prognosis, this disorder is underdiagnosed and undertreated. For these reasons the Italian Society for the Study of Atherosclerosis (SISA) assembled a Consensus Panel with the task to provide guidelines for FH diagnosis and treatment. Data synthesisOur guidelines include: i) an overview of the genetic complexity of FH and the role of candidate genes involved in LDL metabolism; ii) the prevalence of FH in the population; iii) the clinical criteria adopted for the diagnosis of FH; iv) the screening for ASCVD and the role of cardiovascular imaging techniques; v) the role of molecular diagnosis in establishing the genetic bases of the disorder; vi) the current therapeutic options in both heterozygous and homozygous FH. Treatment strategies and targets are currently based on low-density lipoprotein cholesterol (LDL-C) levels, as the prognosis of FH largely depends on the magnitude of LDL-C reduction achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment. Addition of novel medications like PCSK9 inhibitors, ANGPTL3 inhibitors or lomitapide in homozygous FH results in a further reduction of LDL-C levels. LDL apheresis is indicated in FH patients with inadequate response to cholesterol-lowering therapies. ConclusionFH is a common, treatable genetic disorder and, although our understanding of this disease has improved, many challenges still remain with regard to its identification and management.

Acoustic Delivery of Plasma Low-Density Lipoprotein into Liver via ApoB100-Targeted Microbubbles Inhibits Atherosclerotic Plaque Growth.

Atherosclerosis is the main risk factor for cardiovascular disease, which accounts for the majority of mortality worldwide. A significantly increased plasma level of low-density lipoprotein cholesterol (LDL-C), surrounded by a monolayer of phospholipids, free cholesterol, and one apolipoprotein B-100 (ApoB-100) in the blood, plays the most significant role in driving the development of atherosclerosis. Commercially available cholesterol-lowering drugs are not sufficient for preventing recurrent cardiovascular events. Developing alternative strategies to decrease the plasma cholesterol levels is desirable. Herein, we develop an approach for reducing LDL-C levels using gas-filled microbubbles (MBs) that were coated with anti-ApoB100 antibodies. These targeted MBApoB100 could selectively capture LDL particles in the bloodstream through forming LDL-MBApoB100 complexes and transport them to the liver for degradation. Further immunofluorescence staining and lipidomic analyses showed that these LDL-MBApoB100 complexes may be taken up by Kupffer cells and delivered to liver cells and bile acids, greatly inhibiting atherosclerotic plaque growth. More importantly, ultrasound irradiation of these LDL-MBApoB100 complexes that accumulated in the liver may induce acoustic cavitation effects, significantly enhancing the delivery of LDL into liver cells and accelerating their degradation. Our study provides a strategy for decreasing LDL-C levels and inhibiting the progression of atherosclerosis.

IL-1β Inhibition Partially Negates the Beneficial Effects of Diet-Induced Atherosclerosis Regression in Mice.

Thromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions is the global leading cause of death. The most common and effective means to reduce these major adverse cardiovascular events, including myocardial infarction and stroke, is aggressive lipid lowering via a combination of drugs and dietary modifications. However, we know little regarding the effects of reducing dietary lipids on the composition and stability of advanced atherosclerotic lesions, the mechanisms that regulate these processes, and what therapeutic approaches might augment the benefits of lipid lowering. Smooth muscle cell lineage-tracing Apoe-/- mice were fed a high-cholesterol Western diet for 18 weeks and then a zero-cholesterol standard laboratory diet for 12 weeks before treating them with an IL (interleukin)-1β or control antibody for 8 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of smooth muscle cell and other lesion cells by smooth muscle cell lineage tracing combined with single-cell RNA sequencing, cytometry by time-of-flight, and immunostaining plus high-resolution confocal microscopic z-stack analysis. Lipid lowering by switching Apoe-/- mice from a Western diet to a standard laboratory diet reduced LDL cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden, as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1β antibody treatment after diet-induced reductions in lipids resulted in multiple detrimental changes including increased plaque burden and brachiocephalic artery lesion size, as well as increasedintraplaque hemorrhage, necrotic core area, and senescence as compared with IgG control antibody-treated mice. Furthermore, IL-1β antibody treatment upregulated neutrophil degranulation pathways but downregulated smooth muscle cell extracellular matrix pathways likely important for the protective fibrous cap. Taken together, IL-1β appears to be required for the maintenance of standard laboratory diet-induced reductions in plaque burden and increases in multiple indices of plaque stability.

Enhancing Endothelial Function with Nutrient-Enriched Table Hen Eggs: A Randomized Study in Patients Recovering from Acute Coronary Syndrome.

This study investigated the effect of consumption of table eggs enriched with n-3 polyunsaturated fatty acids (n-3 PUFA), lutein, vitamin E and selenium on microvascular function, oxidative stress and inflammatory mediators in patients after acute coronary syndrome (ACS). In a prospective, randomized, interventional, double-blind clinical trial, ACS patients were assigned to either the Nutri4 (N=15, mean age: 57.2±9.2 years), or the Control group (N=13; mean age 56.8±9.6 years). The Nutri4 group consumed three enriched hen eggs daily for three weeks, providing approximately 1.785 mg of vitamin E, 0.330 mg of lutein, 0.054 mg of selenium and 438 mg of n-3 PUFAs. Biochemical parameters, including serum lipids, liver enzymes, nutrient concentrations, serum antioxidant enzyme activity (catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD)), and markers of oxidative stress (thiobarbituric acid reactive substances (TBARS) and ferric reducing ability (FRAP)), were assessed before and after the dietary interventions. Additionally, arterial blood pressure, heart rate, body composition, fluid status, anthropometric measurements, and skin microvascular blood flow responses to various stimuli (postocclusive reactive hyperemia (PORH), acetylcholine- (AchID), and sodium nitroprusside- (SNPID)) were measured using laser Doppler flowmetry (LDF) throughout the study. The intake of Nutri4 eggs led to a significant reduction in LDL cholesterol levels, while the levels of total cholesterol remained within the established reference values. Consuming Nutri4 eggs resulted in a 12.7% increase in serum vitamin E levels, an 8.6% increase in selenium levels, and demonstrated a favorable impact on microvascular reactivity, as evidenced by markedly improved PORH and ACh ID. Nutri4 eggs exerted a significant influence on the activity of GPx and SOD, with no observed changes in TBARS or FRAP values. The consumption of Nutri4 eggs positively influenced microvascular function in individuals with ACS, without eliciting adverse effects on oxidative stress.

Association between pre-treatment with statin and its inhibitory effect on the onset of coronary artery disease at the time of coronary computed tomography angiography: a new look at an old medication.

Coronary artery stenosis is often advanced by the time coronary computed tomography angiography (CCTA). Statins are the most important anti-lipidemic medication for improving the prognosis of coronary artery disease (CAD) patients. Although lipid-lowering therapy using statins appears to have been established as a method for preventing CAD, there remains the problem that CAD cannot be completely suppressed. In this study, we investigated whether pre-treatment with statin could significantly inhibit the onset of CAD when patients received CCTA for screening of CAD. The subjects were 1164 patients who underwent CCTA as screening for CAD. CAD was diagnosed when 50% or more coronary stenosis was present in the coronary arteries. Patient backgrounds were investigated by age, gender, body mass index, coronary risk factors [family history of cardiovascular diseases, smoking history, hypertension (HTN), diabetes mellitus (DM), dyslipidemia, chronic kidney disease (CKD) or metabolic sydrome] and medications. Patients were classified into two groups according to the presence or absence of statin pre-administration during CCTA [statin (-) group (n = 804) and (+) group (n = 360)]. Compared with the statin (-) group, the statin (+) group was significantly older and had higher rates of family history, HTN, and DM. The statin (+) group had a significantly higher % CAD than the statin (-) group. Serum levels of low-density lipoprotein cholesterol (LDL-C) were significantly lower in the statin (+) group than in the statin (-) group. There was no significant difference in either high-density lipoprotein cholesterol levels or triglyceride levels between the two groups. Age, male gender, HTN, DM and pre-treatment with statin were all associated with CAD (+) in all patients. In addition, factors that contributed to CAD (+) in the statin (-) group were age, male gender, and DM, and factors that contributed to CAD (+) in the statin (+) group were age, smoking, HTN and % maximum dose of statin. At the time of CCTA, the statin (+) group had a high rate of CAD and coronary artery stenosis progressed despite a reduction of LDL-C levels. To prevent the onset of CAD, in addition to strict control of other coronary risk factors (HTN etc.), further LDL cholesterol-lowering therapy may be necessary.

Comparative Safety and Efficacy of Low/Moderate-Intensity Statin plus Ezetimibe Combination Therapy vs. High-Intensity Statin Monotherapy in Patients with Atherosclerotic Cardiovascular Disease: An Updated Meta-Analysis.

Statin therapy is considered the gold standard for treating hypercholesterolemia. This updated meta-analysis aims to compare the efficacy and safety of a low/moderate-intensity statin in combination with ezetimibe compared with high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (ASCVD). A systematic search of two databases (PubMed and Cochrane CENTRAL) was conducted from inception to January 2023 and a total of 21 randomized clinical trials (RCTs) were identified and included in the analysis. Data were pooled using Hedges's g and a Mantel-Haenszel random-effects model to derive standard mean differences (SMDs) and 95% confidence intervals (Cis). The primary outcome studied was the effect of these treatments on lipid parameters and safety events. The results revealed that combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels (SMD= -0.41; CI -0.63 to -0.19; P = 0.0002). There was no significant change in the levels of high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TG), high-sensitivity C-reactive protein (hs-CRP), Apo A1, or Apo B. The safety of these treatments was assessed by the following markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine phosphokinase (CK), and a significant difference was only observed in CK (SMD: -0.81; CI -1.52 to -0.10; P = 0.02). This meta-analysis demonstrated that the use of low/moderate-intensity statin combination therapy significantly reduced LDL-C levels compared with high-intensity statin monotherapy, making it preferable for patients with related risks. However, further trials are encouraged to evaluate potential adverse effects associated with combined therapy.

Patient versus physician preferences for lipid-lowering drug therapy: A discrete choice experiment.

The emergence of proprotein convertase subtilisin/kexin type 9 inhibitors offered dyslipidemia patients an alternative to statins for lipid-lowering treatment. Understanding patient and physician preferences for lipid-lowering drugs may promote shared decision-making and improve treatment outcomes. This study utilized an online discrete choice experiment (DCE) to assess the relative importance (RI) of six attributes related to lipid-lowering drugs, including frequency of administration, mode of administration, reduction of low-density lipoprotein cholesterol (LDL-C) level, risk of myopathy, risk of liver damage, and out-of-pocket monthly cost. Respondents were recruited from dyslipidemia patients and cardiovascular physicians in China. A mixed logit model and latent class analysis were employed to estimate the preference coefficient, marginal willingness to pay (mWTP), and RI of attributes. Ethical approval has been obtained for this study. A total of 708 patients and 507 physicians participated in the survey. Patients prioritized the 'risk of liver damage' (RI = 23.6%) with 'mode of administration' (RI = 19.2%) and 'frequency of administration' (RI = 18.8%) following closely. Contrarily, physicians prioritized the 'reduction of LDL-C level' (RI = 33.5%), followed by 'risk of liver damage' (RI = 26.0%) and 'risk of myopathy' (RI = 16.1%). Patients placed a higher value on 'frequency of administration' (p < .001) and 'mode of administration' (p < .001) compared to physicians, while physicians valued 'reduction of LDL-C level' (p < .001) and 'risk of myopathy' (p = .012) more than patients. Physicians exhibited higher mWTP than patients for all attributes except frequency and mode of administration. The LCA revealed three distinct patient classes: focus on oral administration, focus on hepatic safety and frequency and focus on hepatic safety and cost. Likewise, three physician classes were identified: frequency-insensitive, efficacy-focused and safety-focused. The preferences for lipid-lowering drug therapy differed between patients and physicians in China. Physicians should take into account patients' preferences and provide personalized treatment when they formulate lipid-lowering treatment plans. Patients participated in the questionnaire design process. They engaged in a focus group discussion to determine attributes and levels and also participated in a pilot survey to assess the comprehensibility of the questionnaires. Additionally, patients were involved in the DCE survey to express their preferences. The findings of patient preference for lipid-lowering drug therapy will promote shared decision-making and optimize the treatment regimen.

There are those who would like zero LDL cholesterol.

The overwhelming evidence that the reduction of LDL cholesterol (LDLc) levels is associated with a parallel reduction in cardiovascular (CV) risk has led the scientific community to progressively and constantly reduce the optimal therapeutic targets of LDLc, both in patients with known CV disease and in patients undergoing primary prevention. The recent introduction of proprotein convertase subtilisin/kexin type 9 inhibitors has allowed clinicians to observe reductions in LDLc levels that go well beyond the limits set by the main international guidelines; following the 'the lower the better' paradigm, it is natural to ask how low LDLc can be reduced, whether this intervention is associated with a further reduction in CV risk and, above all, whether there are no issues related to safety in the use of polypharmacotherapies that determine an extreme reduction in LDLc levels. The purpose of this article is to summarize the main scientific evidence on the topic, trying to provide an answer to all clinicians who 'would like their LDLc to be-almost-zero'.

Advances in the source, preparation, and application of phytosterols

Phytosterols, also referred to as plant sterols, represent naturally occurring compounds exclusive to the plant kingdom. This comprehensive review delves into the multifaceted realm of phytosterols, encompassing their structural characteristics and physiological functions. A keen focus is placed on elucidating their sources, with an emphasis on their abundance in unprocessed materials. The paper meticulously explores the diverse methods employed in the preparation of phytosterols, concurrently scrutinizing the detection techniques applied in their analysis. Within the medical domain, phytosterols have gained recognition for their efficacy in reducing LDL cholesterol levels, thereby proving instrumental in averting cardiovascular diseases, addressing breast cancer, and managing metabolic disorders. In the cosmetic industry, plant-based oils, enriched with polyunsaturated fatty acids, function as potent antioxidants and moisturizers, counteracting the detrimental effects of free radicals. Furthermore, in the realm of the food industry, phytosterols play a pivotal role in the construction of Nanostructured Lipid Carriers (NLCs), preserving the bioavailability of various compounds. This review article stands out for its synthesis of existing research, offering succinct summaries of each section while adeptly bridging identified research gaps. Its intrinsic value lies in its potential to serve as a crucial resource for researchers, fostering deeper investigations and streamlining research endeavors in the medical, cosmetic, and food sectors.

Safety and Efficacy of PCSK9 Inhibitors in Patients with Acute Coronary Syndrome Who Underwent Coronary Artery Bypass Grafts: A Comparative Retrospective Analysis

Background. The in-hospital reduction in low-density lipoprotein cholesterol (LDL-C) levels following acute coronary syndrome (ACS) is recommended in the current clinical guidelines. However, the efficacy of proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors in those patients undergoing coronary artery bypass graft (CABG) has never been demonstrated. Methods. From January 2022 to July 2023, we retrospectively analyzed 74 ACS patients characterized by higher LDL-C levels than guideline targets and who underwent coronary bypass surgery. In the first period (January 2022–January 2023), the patients increased their statin dosage and/or added Ezetimibe (Group STEZE, 43 patients). At a later time (February 2023–July 2023), the patients received not only statins and Ezetimibe but also Evolocumab 140 mg every 2 weeks starting as early as possible (Group STEVO, 31 patients). After one and three months post-discharge, the patients underwent clinical and laboratory controls with an evaluation of the efficacy lipid measurements and every adverse event. Results. The two groups did not differ in terms of preoperative risk factors and Euroscore II (STEVO: 2.14 ± 0.75 vs. STEZE: 2.05 ± 0.6, p = 0.29). Also, there was no difference between the groups in terms of ACS (ST-, Instable angina, or NSTE) and time of symptoms onset regarding total cholesterol, LDL-C, and HDL-C trends from the preprocedural period to 3-month follow-up, but there was a more significant reduction in LDL-C and total cholesterol in the STEVO group (p = 0.01 and p = 0.04, respectively) and no difference in HDL-C rise (p = 0.12). No deaths were reported. In three STEZE group patients, angina recurrence posed the need for percutaneous re-revascularization. No STEVO patients developed significant adverse events. The statistical difference in these serious events, 7% in STEZE vs. 0% in STEVO, was not significant (p = 0.26). Conclusions. Evolocumab initiated “as soon as possible” in ACS patients submitted to CABG with high-intensity statin therapy and Ezetimibe was well tolerated and resulted in a substantial and significant reduction in LDL-C levels at discharge, 1 month, and 3 months. This result is associated with a reduction but without a statistical difference between groups.

Quantifying the 'distance to LDC-goal' in patients at very high cardiovascular risk with hyperlipidaemia in Germany: a retrospective claims database analysis.

This study quantified the 'distance to LDL-C goal' in patients at very high cardiovascular risk with uncontrolled hyperlipidaemia. 'Distance to LDL-C goal' was defined as the percentage by which low-density lipoprotein cholesterol (LDL-C) levels needed to be reduced to achieve the LDL-C goals specified in the 2016 or 2019 European Society of Cardiology/European Atherosclerosis Society guidelines. This retrospective analysis using data from the IQVIA Disease Analyzer database included patients who were predominantly treated by a primary care physician, diabetologist or cardiologist between 2014 and 2018, with a diagnosis of hyperlipidaemia and an initial LDL-C measurement (index event) and one or more cardiovascular risk factors. The primary outcome was to assess the proportion of patients with uncontrolled hyperlipidaemia and to classify the 'distance to LDL-C goal' in these patients. Data from 32,963 patients were analysed (n = 27,159, n = 3873 and n = 1931 patients in the primary care physician, diabetology and cardiology cohorts, respectively). Most patients had uncontrolled LDL-C levels (⩾70 mg/dL; ⩾1.8 mmol/L) at index (91.0%, 86.4% and 94.0% of patients in the primary care physician, diabetology and cardiology cohorts, respectively). Analysis of the 'distance to LDL-C goal' indicated that approximately one-third of patients in each cohort required an LDL-C level reduction of up to 50% relative to index to achieve their LDL-C goal (35.8%, 43.7% and 28.4% of patients in the primary care physician, diabetology and cardiology cohorts, respectively). LDL-C control was not achieved at 36 months post-index in most patients with uncontrolled LDL-C levels (86.8%, 81.7% and 90.2% of patients in the primary care physician, diabetology and cardiology cohorts, respectively). LDL-C levels were uncontrolled in most patients with hyperlipidaemia. Analysis of the 'distance to LDL-C goal' showed that most patients required a substantial LDL-C level reduction to achieve their LDL-C goal.

A retrospective nationwide analysis of evolocumab use in Sweden and its effect on low-density lipoprotein cholesterol levels.

Treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduces low-density lipoprotein cholesterol (LDL-C) levels and decreases the incidence of major ischaemic events in clinical trials. However, less is known about the efficacy of PCSK9 inhibition in clinical practice. This study aimed to describe the change in LDL-C levels over time and LDL-C goal achievement in patients with/without atherosclerotic cardiovascular disease (ASCVD), who were prescribed evolocumab in clinical practice, and to describe adherence to and persistence with treatment. Patients in Sweden with at least one evolocumab prescription filled between July 2015 and May 2020 were included. Medical history and lipid-lowering therapy (LLT) were sourced from national registries. LDL-C levels before and after treatment initiation were assessed using medical records. Persistence with and adherence to evolocumab and oral LLT were assessed up to 12 months after treatment initiation using the refill-gap method and proportion of days covered, respectively. Of the 2,360 patients with at least one prescription for evolocumab, 2,341 were included; 1,858 had ASCVD. Persistence with (76%) and adherence to (86%) evolocumab were high throughout the 12 months following initiation. Mean LDL-C levels decreased by 53% (95% confidence interval [CI]: 51-55%) in patients adherent to evolocumab (n = 567) and 59% (95% CI: 55-63%) in patients adherent to evolocumab and oral LLT (n = 186). Similar reductions in LDL-C were observed in patients with/without ASCVD. Reduced LDL-C levels remained stable during follow-up. Amongst patients adherent to evolocumab and those adherent to evolocumab and oral LLT, 23 and 55% achieved the LDL-C goal of <1.4 mmol/L, respectively. The evolocumab LDL-C-lowering effect observed in clinical trials was confirmed in clinical practice in Sweden, particularly in patients also treated with oral LLT. During follow-up, adherence to and persistence with evolocumab were high, with stable reduced levels of LDL-C during observation.

Evinacumab (Evkeeza)

&#x0D; CADTH recommends that Evkeeza be reimbursed by public drug plans as an adjunct to diet and other low-density lipoprotein cholesterol (LDL-C)–lowering therapies for the treatment of adult and pediatric patients aged 5 years and older with homozygous familial hypercholesterolemia (HoFH) if certain conditions are met.&#x0D; Evkeeza should only be covered to treat patients aged 5 years and older with a diagnosis of HoFH and extremely high levels of LDL-C (sometimes referred to as bad cholesterol) despite receiving other cholesterol-lowering treatments.&#x0D; Evkeeza should only be reimbursed if prescribed by specialists with experience in managing HoFH and if the cost of Evkeeza is reduced. Evkeeza may only be prescribed for 24 weeks the first time it is used. To continue treatment with Evkeeza longer than 6 months, the treating physician must provide proof that the patient is responding to treatment, defined as reduction in LDL-C levels.&#x0D;

Oreo Cookie Treatment Lowers LDL Cholesterol More Than High-Intensity Statin therapy in a Lean Mass Hyper-Responder on a Ketogenic Diet: A Curious Crossover Experiment.

Recent research has identified a unique population of 'Lean Mass Hyper-Responders' (LMHR) who exhibit increases in LDL cholesterol (LDL-C) in response to carbohydrate-restricted diets to levels ≥ 200 mg/dL, in association with HDL cholesterol ≥ 80 mg/dL and triglycerides ≤ 70 mg/dL. This triad of markers occurs primarily in lean metabolically healthy subjects, with the magnitude of increase in LDL-C inversely associated with body mass index. The lipid energy model has been proposed as one explanation for LMHR phenotype and posits that there is increased export and subsequent turnover of VLDL to LDL particles to meet systemic energy needs in the setting of hepatic glycogen depletion and low body fat. This single subject crossover experiment aimed to test the hypothesis that adding carbohydrates, in the form of Oreo cookies, to an LMHR subject on a ketogenic diet would reduce LDL-C levels by a similar, or greater, magnitude than high-intensity statin therapy. The study was designed as follows: after a 2-week run-in period on a standardized ketogenic diet, study arm 1 consisted of supplementation with 12 regular Oreo cookies, providing 100 g/d of additional carbohydrates for 16 days. Throughout this arm, ketosis was monitored and maintained at levels similar to the subject's standard ketogenic diet using supplemental exogenous d-β-hydroxybutyrate supplementation four times daily. Following the discontinuation of Oreo supplementation, the subject maintained a stable ketogenic diet for 3 months and documented a return to baseline weight and hypercholesterolemic status. During study arm 2, the subject received rosuvastatin 20 mg daily for 6 weeks. Lipid panels were drawn water-only fasted and weekly throughout the study. Baseline LDL-C was 384 mg/dL and reduced to 111 mg/dL (71% reduction) after Oreo supplementation. Following the washout period, LDL-C returned to 421 mg/dL, and was reduced to a nadir of 284 mg/dL with 20 mg rosuvastatin therapy (32.5% reduction). In conclusion, in this case study experiment, short-term Oreo supplementation lowered LDL-C more than 6 weeks of high-intensity statin therapy in an LMHR subject on a ketogenic diet. This dramatic metabolic demonstration, consistent with the lipid energy model, should provoke further research and not be seen as health advice.

Impact of Bempedoic Acid on Total Cardiovascular Events

The ATP citrate lyase (ACL) inhibitor, bempedoic acid, reduces low-density lipoprotein cholesterol (LDL-C) level and major adverse cardiovascular events (MACE) by 13% in patients at high cardiovascular risk with intolerance of statin and high-intensity statin medications. The effects of bempedoic acid on total cardiovascular events remain unknown. To determine the impact of bempedoic acid on the total incidence of MACE. Included in this prespecified analysis of the Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes trial were patients with, or at high risk for, cardiovascular disease, with hypercholesterolemia and inability to take guideline-recommended statins. Study data were analyzed from December 2016 to November 2022. Patients were randomly assigned to treatment with bempedoic acid or placebo daily. The primary end point was the time to first event for a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization (MACE-4). The key secondary end point was time to first event for cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (MACE-3). This prespecified analysis compared the total number of cardiovascular events in the treatment groups. A total of 13 970 patients (mean [SD] age, 65 [9] years; 7230 male [51.8%]) were included in the study. A total of 9764 participants (69.9%) had prior atherosclerotic cardiovascular disease and a baseline LDL-C level of 139 mg/dL; treatment with bempedoic acid resulted in a 21% reduction in LDL-C level and a 22% reduction in high-sensitivity C-reactive protein (hsCRP) level at 6 months. Median (IQR) follow-up was 3.4 (3.1-3.9) years. A total of 1746 positively adjudicated first MACE-4 events and 915 additional MACE events in 612 patients were recorded, with coronary revascularization representing 32.8% (573 of 1746) of first events and 69.4% (635 of 915) of additional events. For the total incidence of cardiovascular events, treatment with bempedoic acid was associated with a reduction in risk of MACE-4 (hazard ratio [HR], 0.80; 95% CI, 0.72-0.89; P <.001), MACE-3 (HR, 0.83; 95% CI, 0.73-0.93; P = .002), myocardial infarction (HR, 0.69; 95% CI, 0.58-0.83; P < .001), and coronary revascularization (HR, 0.78; 95% CI, 0.68-0.89; P <.001), although no statistically significant difference was observed for stroke (HR, 0.80; 95% CI, 0.63-1.03). A lower HR for protection with bempedoic acid was observed with increasing number of MACE events experienced by patients. Lowering LDL-C level with bempedoic acid reduced the total number of cardiovascular events in patients with high cardiovascular risk, statin therapy intolerance, and elevated LDL-C levels.