Conventional Lipid-lowering Therapies Research Articles

Unmasking a Case of Sitosterolaemia: An Approach for Diagnosis and Management.

Recognise the significance of considering sitosterolaemia in differential diagnosis for unexplained lipid abnormalities.Understand the challenges in diagnosing and managing sitosterolaemia, especially in patients with atypical responses to conventional lipid-lowering therapies.

Abstract 158: The Role Of Ehbp1 In Hypercholesterolemia

Background: Despite aggressive lowering of cholesterol, conventional lipid-lowering therapies only modestly lower cardiovascular risk in the population. Therefore, identifying novel hypercholesterolemia-risk targets is of critical importance. Human genome-wide association studies (GWAS) have revealed that several single-nucleotide polymorphisms (SNPs) in EHBP1 , the gene that encodes EH domain binding protein 1 (EHBP1), an endocytic trafficking regulator, are associated with serum cholesterol. However, the mechanisms underlying this association and the role of EHBP1 in cholesterol metabolism are unknown. We hypothesize that EHBP1 is a novel hypercholesterolemia risk factor. The goal of this study is to explore the role of EHBP1 in hypercholesterolemia and its underlying mechanisms. Methods: Hepatocyte EHBP1 was silenced by intravenous injection (IV) of AAV8-H1-shEhbp1 in wild-type (WT), Apoe-/- and Ldlr-/- mice, followed by Western Diet feeding to induce hypercholesterolemia and atherosclerosis. Primary murine and human hepatocytes were isolated for in vitro mechanistic studies. We also leveraged publicly available human genetic studies and unbiased scRNA datasets to support our study. Results: Individuals with the EHBP1 rs10496099 T>C variant have decreased serum cholesterol and reduced liver EHBP1 expression. Consistent with the human data, our in vivo study with hypercholesterolemic mice shows that EHBP1 silencing in hepatocytes decreases plasma total and LDL/VLDL cholesterol. Our in vitro study with primary hepatocytes reveals that EHBP1 deficiency eliminates sortilin (SORT1)-mediated PCSK9 secretion and induces LDLR-mediated LDL uptake. Mechanistically, we found that EHBP1 silencing abolishes the homeostasis of the retromer complex, a protein complex that helps retrograde and stabilize sortilin. Conclusion: Hepatocyte EHBP1 promotes sortilin-mediated PCSK9 secretion by maintaining retromer homeostasis, leading to LDLR degradation and hypercholesterolemia. Our study elucidates a novel link between EHBP1 and other cholesterol-associated loci (e.g., SORT1 , PCSK9 , and LDLR) and provides new mechanistic insight into the role of EHBP1 in hepatic cholesterol metabolism and hypercholesterolemia.

Abstract 12279: Cardiovascular Disease Progression in Children With Homozygous Familial Hypercholesterolemia Despite Early Diagnosis on a Genetic Cascade Screening Program

Introduction: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated low-density lipoprotein cholesterol (LDL-c) and very high risk of premature atherosclerotic cardiovascular (ASCVD) and aortic/supraortic valve heart diseases (VHD). The study aim was to examine clinical and biochemical trajectories of a cohort of HoFH patients since childhood. Methods: In this longitudinal study we assessed the incidence of manifest or subclinical ASCVD (coronary or carotid) and VHD as well as plasma lipids in a cohort of HoFH subjects during a 12.9 ± 9.6 years follow-up. Results: From the 868 individuals ≤19 y-old (at baseline) that were genotyped on a genetic cascade screening program, 420 (48.4%) had an FH mutation. From children bearing mutations, 12 were true homozygotes and 1 was compound heterozygote (53.8% females, mean age 7.5 ± 4.1 years at the first visit). During follow-up all were on statin and ezetimibe therapies, and the mean final dose of atorvastatin was 56 ± 27 mg/d (n=10); and rosuvastatin, 26 ± 17 mg/d (n=3). Initial and on treatment LDL-c were 655 ± 177 mg/dL and 399 ± 150 mg/dL, respectively, with a mean 39.1% reduction (-256 mg/dL). None were under LDL apheresis; 2 patients used mipomersen, 2 lomitapide, and 2 are currently using PCSK9 inhibitors. Subclinical cardiovascular disease, either coronary, carotid or in aortic valve, was identified in 38.5% (n=5; mean age 16.4 ± 9.8 years), whereas 30.8% had a clinical cardiovascular event (n=4; mean age 22.8 ± 6.8 years), with 2 deaths. Therefore, 69.3% had either subclinical or manifest cardiovascular disease. Conclusion: Despite early diagnosis and LDL-c reduction HoFH is still marked by an adverse and premature cardiovascular disease progression. Conventional lipid lowering therapies are not adequate to prevent ASCVD and VHD disease course.

Lessons learned from the evinacumab trials in the treatment of homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a life-threatening disease characterized by extremely elevated LDL cholesterol (LDL-C) levels which result in premature atherosclerotic cardiovascular disease. As conventional lipid-lowering therapies, which mainly depend on LDL receptors for LDL particle clearance, remain insufficient for reaching the recommended LDL-C levels in HoFH, agents acting independently of LDL receptors, such as ANGPTL3 inhibitors, constitute a promising target. Evinacumab, a monoclonal antibody directed against ANGPTL3, was approved in the USA in 2021 for treating patients with HoFH. Evinacumab has shown an adequate safety profile with strong LDL-lowering efficacy. This review highlights the development path of evinacumab and provides insight on the lessons learned from trials as well as the hurdles facing accessibility.

Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey

BackgroundHomozygous familial hypercholesterolemia (HoFH) is a rare life-threatening condition that represents a therapeutic challenge. The vast majority of HoFH patients fail to achieve LDL-C targets when treated with the standard protocol, which associates maximally tolerated dose of lipid-lowering medications with lipoprotein apheresis (LA). Lomitapide is an emerging therapy in HoFH, but its place in the treatment algorithm is disputed because a comparison of its long-term efficacy versus LA in reducing LDL-C burden is not available. We assessed changes in long-term LDL-C burden and goals achievement in two independent HoFH patients’ cohorts, one treated with lomitapide in Italy (n = 30) and the other with LA in France (n = 29).ResultsThe two cohorts differed significantly for genotype (p = 0.004), baseline lipid profile (p < 0.001), age of treatment initiation (p < 0.001), occurrence of cardiovascular disease (p = 0.003) as well as follow-up duration (p < 0.001). The adjunct of lomitapide to conventional lipid-lowering therapies determined an additional 58.0% reduction of last visit LDL-C levels, compared to 37.1% when LA was added (padj = 0.004). Yearly on-treatment LDL-C < 70 mg/dl and < 55 mg/dl goals were only achieved in 45.5% and 13.5% of HoFH patients treated with lomitapide. The long-term exposure to LDL-C burden was found to be higher in LA than in Lomitapide cohort (13,236.1 ± 5492.1 vs. 11,656.6 ± 4730.9 mg/dL-year respectively, padj = 0.002). A trend towards fewer total cardiovascular events was observed in the Lomitapide than in the LA cohort.ConclusionsIn comparison with LA, lomitapide appears to provide a better control of LDL-C in HoFH. Further studies are needed to confirm this data and establish whether this translates into a reduction of cardiovascular risk.

Evolving trend in the management of heterozygous familial hypercholesterolemia in Italy: A retrospective, single center, observational study

Background and aimsThe effective reduction of LDL-C in patients with heterozygous familial hypercholesterolemia (HeFH) is crucial to reduce their increased cardiovascular risk. Diagnostic and therapeutic (PCSK9 inhibitors) tools to manage HeFH improved in recent years. However, the impact of these progresses in ameliorating the contemporary real-world care of these patients remains to be determined. Aim of this study was to assess the evolution of treatments and LDL-C control in a cohort of HeFH patients in Italy. Methods and resultsFour hundred six clinically diagnosed HeFH followed in a single, tertiary lipid centre were included in this survey. Data on lipid levels and medications were collected at baseline and during a median 3-year follow-up. At baseline, 19.8% of patients were receiving conventional high-potency lipid lowering therapies (LLT) and this percentage increased up to 50.8% at last visit. The knowledge of results of molecular diagnosis was associated with a significant increase in treatment intensity and LDL-C lowering. Nevertheless, the new LDL-C target (<70 mg/dl) was achieved only in 3.6% of HeFH patients under conventional LLTs and this proportion remained low (2.9%) also in those exposed to maximal conventional LLT. In 51 patients prescribed with PCSK9 inhibitors, 64.6% and 62.1% reached LDL-C<70 mg/dl at 3- and 12-month follow-up, respectively. ConclusionsAlthough treatments of HeFH improved over time, LDL-C target achievement with conventional LLT remains poor, mainly among women. The use of molecular diagnosis and even more the prescription of PCSK9i may improve LDL-C control in these patients.

Autosomal recessive hypercholesterolemia: update for 2020.

This review summarizes the current knowledge regarding autosomal recessive hypercholesterolemia (ARH) and provides new insight into the natural history and therapeutic management of this lipid disorder. Novel homozygous and compound heterozygous ARH-causing mutations have been reported in the literature, to date. The long-term follow-up of a cohort of ARH patients demonstrated that, despite intensive treatment with conventional lipid-lowering therapies, their low-density lipoprotein (LDL) cholesterol levels remain far from target and this translates into a poor cardiovascular prognosis. ARH is also associated with increased risk of developing aortic valve stenosis. However, lomitapide, a microsomal triglyceride transfers protein inhibitor, may represent a new opportunity for the effective treatment of ARH. ARH is an ultrarare disorder of LDL metabolism caused by mutations in the LDLRAP1 gene. It is inherited as a recessive trait and causative mutations, though heterogeneous, are all predicted to be loss-of-function. Recent investigations have demonstrated that ARH can be considered a phenocopy of homozygous familial hypercholesterolemia, where the risk of atherosclerotic cardiovascular diseases and aortic valve stenosis remains elevated despite conventional therapies. The combination of lomitapide with the conventional LDL-C-lowering medications appears to be a promising approach to treat this condition.

Lipid Lowering Treatment and Eligibility for PCSK9 Inhibition in Post-Myocardial Infarction Patients in Italy: Insights from Two Contemporary Nationwide Registries.

Introduction The current use of lipid lowering therapies and the eligibility for proprotein convertase subtilisin/kexin-9 (PCSK9) inhibitors of patients surviving a myocardial infarction (MI) is poorly known. Methods Using the data from two contemporary, nationwide, prospective, real-world registries of patients with stable coronary artery disease, we sought to describe the lipid lowering therapies prescribed by cardiologists in patients with a prior MI and the resulting eligibility for PCSK9 inhibitors according to the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) and the Italian regulatory agency (Agenzia Italiana del Farmaco; AIFA) criteria. The study cohort was stratified according to the following low-density lipoprotein cholesterol (LDL-C) levels at the time of enrolment: <70 mg/dl; 70–99 mg/dl and ≥100 mg/dl. Results Among the 3074 post-MI patients with LDL-C levels available, a target level of LDL-C < 70 mg/dl was present in 1186 (38.6%), while 1150 (37.4%) had LDL-C levels ranging from 70 to 99 mg/dl and the remaining 738 (24.0%) an LDL-C ≥ 100 mg/dl. A statin was prescribed more frequently in post-MI patients with LDL-C levels <70 mg/dl (97.1%) compared to the other LDL-C groups (p < 0.0001). A low dose of statin was prescribed in 9.3%, while a high dose in 61.4% of patients. Statin plus ezetimibe association therapy was used in less than 18% of cases. In the overall cohort, 293 (9.8%) and 450 (22.2%) resulted eligible for PCSK9 inhibitors, according to ESC/EAS and AIFA criteria, respectively. Conclusions Post-MI patients are undertreated with conventional lipid lowering therapies. A minority of post-MI patients would be eligible to PCSK9 inhibitors according to ESC/EAS guidelines and Italian regulatory agency criteria.

Current Drugs and Nutraceuticals for the Treatment of Patients with Dyslipidemias.

Coronary heart disease (CHD) remains the leading cause of disability and death in industrialized Countries. Among many conditions, which contribute to the etiology and progression of CHD, the presence of high low density lipoprotein-cholesterol (LDL-C) levels represents the major risk factor. Therefore, the reduction of LDL-C levels plays a key role in the management of patients with high or very high cardiovascular risk. Although statins represent the gold standard therapy for the reduction of cholesterol levels, these drugs do not allow to achieve target levels of LDL-C in all patients. Indeed, a significant number of patients resulted intolerants, especially when the dosage increased. The availability of new lipid-lowering drugs, such as ezetimibe and PCSK9 inhibitors, may represent an important alternative or complement to the conventional lipid-lowering therapies. However, long-term studies are still needed to define both efficacy and safety of use of these latter new drugs. Some nutraceuticals may become an adequate and effective support in the management of some patients. To date, several nutraceuticals with different mechanism of actions that provide a good tolerability are available as lipidlowering agents. In particular, the most investigated are red yeast rice, phytosterols, berberine, beta-glucans and soy. The aim of this review was to report recent data on the efficacy and safety of principle hypocholesterolemic drugs available and to evaluate the possible role of some nutraceuticals as support therapy in the management of patients with dyslipidemias.

Angiopoietin-Like 3 (ANGPTL3) and Atherosclerosis: Lipid and Non-Lipid Related Effects.

Genetic and clinical studies have demonstrated that loss-of-function variants in the angiopoietin-like 3 (ANGPTL3) gene are associated with decreased plasma levels of triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), which leads to a significant reduction in cardiovascular risk. For this reason, ANGPTL3 is considered an important new pharmacological target for the treatment of cardiovascular diseases (CVDs) together with more conventional lipid lowering therapies, such as statins and anti proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies. Experimental evidence demonstrates that anti-ANGPTL3 therapies have an important anti-atherosclerotic effect. Results from phase I clinical trials with a monoclonal anti-ANGPTL3 antibody (evinacumab) and anti-sense oligonucleotide (ASO) clearly show a significant lipid lowering effect. In addition, from the analysis of the protein structure of ANGPTL3, it has been hypothesized that, beyond its inhibitory activity on lipoprotein and endothelial lipases, this molecule may have a pro-inflammatory, pro-angiogenic effect and a negative effect on cholesterol efflux, implying additional pro-atherosclerotic properties. In the future, data from phase II clinical trials and additional experimental evidence will help to define the efficacy and the additional anti-atherosclerotic properties of anti-ANGPTL3 therapies beyond the already available lipid lowering therapies.

Long-Term Efficacy and Safety of the Microsomal Triglyceride Transfer Protein Inhibitor Lomitapide in Patients With Homozygous Familial Hypercholesterolemia

Homozygous familial hypercholesterolemia is a genetic disorder characterized by low-density lipoprotein (LDL)-receptor dysfunction, markedly elevated levels of LDL-cholesterol (LDL-C) and premature atherosclerosis. Patients are often poorly responsive to conventional lipid-lowering therapies that upregulate LDL-receptor expression.1 Lomitapide inhibits microsomal triglyceride transfer protein, which lipidates nascent apolipoprotein (apo)B-containing lipoproteins. In a pivotal 78-week open-label trial, lomitapide, titrated to the maximal tolerable dose, decreased LDL-C by 50% at the end of the efficacy phase (week 26) in patients with homozygous familial hypercholesterolemia.2 The principal adverse events included gastrointestinal disturbances, hepatic enzyme elevations, and increased liver fat. Here we provide additional long-term efficacy and safety data, including an exploratory analysis of the potential metabolic consequences of hepatic fat accumulation from an extension trial (NCT00943306). Patients continued on lomitapide at the maximally tolerated dose until transition to commercial or compassionate lomitapide. Lipid-lowering therapies, including apheresis, could be modified at the investigator’s discretion if LDL-C was <100 mg/dL. Both studies received institutional review board and regulatory approval, and all participants provided informed consent. Significance of the percent changes from baseline was assessed using a mixed linear model; correlations were assessed with Pearson correlation. Nineteen (mean age, 30.4 years; 10 male/9 female) of the 23 patients who completed the pivotal trial enrolled in the extension trial, and 17 completed week 126 (78 weeks pivotal + 48 weeks extension) assessments (primary efficacy end point). Three patients discontinued prematurely (relocation, elevated transaminases and excess alcohol, sudden cardiac death). The median lomitapide dose remained mostly consistent at 40 mg (range, 20–60 mg) from week 36 in the pivotal study to week 282 in the extension trial. Overall, the median treatment duration with lomitapide across both trials was 5.1 years (range, 2.1–5.7 years). Among the 17 patients who completed week 126, LDL-C decreased from 356±127 mg/dL at baseline to …

Pharmacological Effects of Niacin on Acute Hyperlipemia.

The well-known changes in modern lifestyle habits including over nutrition and physical inactivity have led to striking adverse effects on public health (e.g., obesity, diabetes, and metabolic syndrome) over recent decades. One noticeable consequence is exaggerated and prolonged state of postprandial hyperlipemia due to the ingestion of multiple fat-enriched meals during the course of a day. Postprandial (non-fasting) hyperlipemia is characterized by increased blood levels of exogenous triglycerides (TG) in the form of apolipoprotein (apo) B48-containing TG-rich lipoproteins (TRL), which have a causal role in the pathogenesis and progression of cardiovascular disease (CVD). The cardiovascular benefits of lifestyle modification (healthy diet and exercise) and conventional lipid-lowering therapies (e.g., statins, fibrates, and niacin) could involve their favourable effects on postprandial metabolism. Pharmacologically, niacin has been used as an athero-protective drug for five decades. Studies have since shown that niacin may decrease fasting levels of plasma verylow- density lipoproteins (VLDL), low-density lipoprotein cholesterol (LDL-C), and lipoprotein [a] (Lp[a]), while may increase high-density lipoprotein cholesterol (HDL-C). Herein, the purpose of this review was to provide an update on effects and mechanisms related to the pharmacological actions of niacin on acute hyperlipemia.

Metreleptin for metabolic disorders associated with generalized or partial lipodystrophy

Lipodystrophy is a group of acquired and inherited disorders characterized by selective loss of adipose tissue. Despite wide genotypic and phenotypic variety, many patients with lipodystrophy have similar metabolic complications including insulin resistance, diabetes mellitus, hypertriglyceridemia and hepatic steatosis. Often, these metabolic abnormalities are severe and difficult to treat with conventional glucose and lipid-lowering therapies. Lack of adipose tissue also results in marked hypoleptinemia, and there has recently been much interest in using leptin-replacement therapy to treat the metabolic complications of lipodystrophy. Administration of metreleptin, the human recombinant leptin analogue, has been shown in prospective, open-label studies to improve glucose control, dyslipidemia and steatohepatitis. This article summarizes the current evidence for the safety and efficacy of leptin-replacement therapy in patients with lipodystrophy.

Postprandial Hypertriglyceridemia and Cardiovascular Disease: Current and Future Therapies

Exaggerated postprandial hypertriglyceridemia is a risk factor for cardiovascular disease. This metabolic abnormality is principally due to overproduction and/or decreased catabolism of triglyceride-rich lipoproteins (TRLs) and is a consequence of pathogenic genetic variations and other coexistent medical conditions, particularly obesity and insulin resistance. Accumulation of TRL in the postprandial state promotes the formation of small, dense low-density lipoproteins, as well as oxidative stress, inflammation, and endothelial dysfunction, all of which compound the risk of cardiovascular disease. The cardiovascular benefits of lifestyle modification (weight loss and exercise) and conventional lipid-lowering therapies (statins, fibrates, niacin, ezetimibe, and n-3 fatty acid supplementation) could involve their favorable effects on TRL metabolism. New agents, such as dual peroxisome-proliferator-activated receptor α/δ agonists, diacylglycerol, inhibitors of diacylglycerol acyltransferase 1 and microsomal triglyceride transfer protein, antisense oligonucleotides for apolipoprotein B-100 and apolipoprotein C-III, and incretin-based therapies, may enhance the treatment of postprandial lipemia, but their efficacy needs to be tested in clinical end point trials. Further work is required to develop a simple clinical protocol for investigating postprandial lipemia, as well as internationally agreed management guidelines for this type of dyslipidemia.