The Long-Term Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia.

Background: Homozygous familial hypercholesterolemia (HoFH) is characterized by early-onset atherosclerotic cardiovascular disease due to the high low-density lipoprotein cholesterol (LDL-C) burden. Patients with null-null low-density lipoprotein receptor () variants respond poorly, if at all, to statins and proprotein convertase subtilisin/kexin type 9 inhibitors, which act by upregulating expression. The 24-week double-blind treatment period (DBTP) of the phase 3 ELIPSE HoFH (Evinacumab Lipid Studies in Patients with Homozygous Familial hypercholesterolemia; NCT03399786) study demonstrated significant LDL-C reductions in patients with HoFH; LDL-C reductions were also observed in those with null-null mutations.

Comparison of the burden of familial hypercholesterolemia between two cohorts of French Canadians hospitalized 25 years apart for coronary heart disease.

Background: Familial hypercholesterolemia (FH) is associated with lifelong elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). Clinical recommendations and treatments have emerged to facilitate the management of FH patients. Their impact on the burden of FH is however not well documented.

Longer-Term Efficacy and Safety of Evinacumab in Patients With Refractory Hypercholesterolemia.

Importance: Patients with refractory hypercholesterolemia who do not achieve their guideline-defined low-density lipoprotein cholesterol (LDL-C) thresholds despite treatment with maximally tolerated combinations of lipid-lowering therapies (LLTs) have an increased risk of atherosclerotic cardiovascular disease (ASCVD).

Objective: To evaluate longer-term efficacy and safety of evinacumab in patients with refractory hypercholesterolemia.

Design, Setting, And Participants: This randomized clinical trial included a 2-week screening period followed by a 16-week double-blind treatment period (DBTP) for subcutaneous regimens (evinacumab, 450 mg, once weekly [QW]; evinacumab, 300 mg, QW; evinacumab, 300 mg, every 2 weeks; or placebo QW) or a 24-week DBTP for intravenous regimens (evinacumab, 15 mg/kg, every 4 weeks [Q4W]; evinacumab, 5 mg/kg, Q4W; or placebo Q4W); a 48-week open-label treatment period (OLTP) for intravenous treatment only; and a 24-week follow-up period.

Homozygous Familial Hypercholesterolemia in Canada: An Observational Study.

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by very high levels of low-density lipoprotein cholesterol (LDL-C). Untreated patients present with extensive xanthomas and premature atherosclerosis. Lipid-lowering therapy is highly efficacious and has dramatically increased life expectancy of patients with HoFH.

Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial.

Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations (n = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations (n = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations (n = 19).

Correlation between chylomicronemia diagnosis scores and post-heparin lipoprotein lipase activity.

Introduction: Sustained chylomicronemia is a defect in post-prandial triglyceride management characterized by severe hypertriglyceridemia (triglyceride > 10 mmol/L) due to functional or genetic defects in lipoprotein lipase (LPL)-mediated triglyceride-rich lipoprotein lipolysis. Familial chylomicronemia syndrome (FCS) is a rare mendelian form of chylomicronemia caused by loss-of-function variants in LPL or LPL-related genes. Most individuals with chylomicronemia however present multifactorial chylomicronemia (MCS), in which LPL bio-availability and activity are variable.

Atherosclerotic plaque regression in homozygous familial hypercholesterolaemia: a case report of a long-term lipid-lowering therapy involving LDL-receptor-independent mechanisms.

Background: Homozygous familial hypercholesterolaemia (HoFH) is a rare and life-threatening genetic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels, important xanthomatosis and increased risk of premature atherosclerotic cardiovascular disease. Management of HoFH at an early stage is recommended but conventional lipid-lowering therapies (LLTs) dependent on the LDL-receptor for clearance of LDL particles, are usually not sufficient. However, agents acting independently of the LDL-receptor, such as inhibitors of microsomal triglyceride transfer protein (MTP) or angiopoietin-like protein 3 (ANGPTL3), administered in combination, on top of standard-of-care LLT constitute a promising therapy for HoFH.

Comparison of Three Methods for LDLC Calculation for Cardiovascular Disease Risk Categorisation in Three Distinct Patient Populations.

Background: Limitations of the Friedewald equation for low-density-lipoprotein cholesterol (F-LDLC) calculation led to the Martin-Hopkins (M-LDLC) and Sampson-National Institutes of Health (S-LDLC) equations. We studied these newer calculations of LDLC for correlation and discordance for stratification into the Canadian Cardiovascular Society (CCS) 2021 Dyslipidemia Guidelines' cardiovascular disease (CVD) risk categories.

Methods: We performed analyses on lipid profiles from 3 populations: records of a hospital biochemistry laboratory (population 1), lipid clinic patients without select monogenic dyslipidemias (population 2A), and lipid clinic patients with familial hypercholesterolemia (FH; population 2B).

Palmar Striated Xanthomas in Clinical Practice.

Context: Palmar striated xanthomas (PSX) are macular subcutaneous lesions conferring a yellow-to-orange coloration of palmar and finger creases that characterize dysbetalipoproteinemia, a disease associated with sustained plasma accumulation of triglyceride-rich lipoprotein remnants. Although remnants accumulation may occur in any condition interfering with triglyceride-rich lipoprotein hydrolysis or clearance, the presence of PSX has not been systematically assessed across the spectrum of lipid disorders potentially associated with sustained or recurrent remnants accumulation.

Objective: The aim of this study was to assess the occurrence of (PSX) in a wide spectrum of lipid disorders ranging from very severe hypercholesterolemia (homozygous familial hypercholesterolemia) to very severe hypertriglyceridemia (chylomicronemia).

A More Atherogenic Lipoprotein Status Is Present in Adults With Type 2 Diabetes Mellitus Than in Those Without With Equivalent Degrees of Hypertriglyceridemia.

Objectives: The impact of type 2 diabetes (T2DM) on biomarkers denoting lipoprotein compositional status was studied in mild and moderate hypertriglyceridemia (HTG). Diabetic dyslipidemia pathophysiology could contribute to differences in lipoprotein compositional status, which could be reflected in the preferred cardiovascular disease risk prediction markers in HTG: non-high-density lipoprotein cholesterol (non-HDLC) and apolipoprotein B (apoB).

Methods: A total of 2,775 fasting lipid profiles from a tertiary care lipid clinic were analyzed as 2 subgroups (with and without T2DM), stratified by triglyceride (TG) levels: normotriglyceridemia (TG 0.

SARS-CoV-2 Receptor ACE2 Gene Is Associated with Hypertension and Severity of COVID 19: Interaction with Sex, Obesity, and Smoking.

Background: Angiotensin-converting enzyme 2 (ACE2) has been identified as the entry receptor for coronaviruses into human cells, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Since hypertension (HT) is a leading comorbidity in non-survivors of COVID-19, we tested for association between ACE2 gene and HT in interaction with specific pre-existing conditions known to be associated with COVID-19 severity.

Methods: Genetic analysis of ACE2 gene was conducted in French-Canadian (FC) and British populations.

Evinacumab in Patients with Refractory Hypercholesterolemia.

Background: Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known.

Methods: In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis.

Relative effect of hypertriglyceridemia on non-HDLC and apolipoprotein B as cardiovascular disease risk markers.

Background: Non-high density lipoprotein cholesterol (non-HDLC) represents the cholesterol in triglyceride-rich lipoproteins (TRL) and low-density lipoproteins (LDL). Apolipoprotein B (apoB) reflects the number of TRL and LDL particles. In hypertriglyceridemia (HTG), there is triglyceride (TG) enrichment of TRLs, and also a substantial increase of cholesterol in larger TRLs that considerably augments the non-HDLC value.

Evinacumab for Homozygous Familial Hypercholesterolemia.

Background: Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 () are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease.

Gene expression profiles of recurrent acute pancreatitis risk in patients with sustained chylomicronemia.

A fasting triglyceridemia >10 mmol/L is associated with chylomicronemia (CM) and an increased recurrent acute pancreatitis (RAP) risk. The number of pancreatitis episodes varies significantly between patients with CM. The objective of this study was to investigate gene expression profiles of RAP in patients with CM.

Dissection of Clinical and Gene Expression Signatures of Familial versus Multifactorial Chylomicronemia.

Familial chylomicronemia syndrome (FCS) is a rare disorder associated with chylomicronemia (CM) and an increased risk of pancreatitis. Most individuals with CM do not have FCS but exhibit multifactorial CM (MCM), which differs from FCS in terms of risk and disease management. This study aimed to investigate clinical and gene expression profiles of FCS and MCM patients.

Calculated Non-HDL Cholesterol Includes Cholesterol in Larger Triglyceride-Rich Lipoproteins in Hypertriglyceridemia.

Context: Calculated non-high-density lipoprotein (HDL) cholesterol (non-HDLC) should selectively include cholesterol from atherogenic lipoproteins to be a reliable risk marker of cardiovascular disease. In hypertriglyceridemia (HTG), there is increased abundance of larger and less atherogenic triglyceride-rich lipoproteins (TRL), namely, larger very-low-density lipoproteins (VLDL), and chylomicrons.

Objective: We aim to demonstrate that serum triglyceride (TG) level has a substantial impact on non-HDLC's ability to represent cholesterol from atherogenic lipoproteins, even though TG is not part of the calculation for non-HDLC.

Preclinical discovery and development of evolocumab for the treatment of hypercholesterolemia.

: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that binds and promotes the lysosomal degradation of the low-density lipoprotein receptors (LDLR). Upon its discovery in 2002, PCSK9 inhibition has subsequently emerged as a novel target for lowering LDL-cholesterol (LDL-C) and reducing coronary heart disease. Evolocumab, a monoclonal antibody directed against human PCSK9, was approved in 2015 as an adjunct to lipid-lowering therapy for treating patients with familial hypercholesterolemia (FH) or patients with high cardiovascular risk, who are treated with maximally tolerated lipid-lowering agents and have not reached the recommended LDL-C levels.

Functional Analysis of LDLR (Low-Density Lipoprotein Receptor) Variants in Patient Lymphocytes to Assess the Effect of Evinacumab in Homozygous Familial Hypercholesterolemia Patients With a Spectrum of LDLR Activity.

Objective: Homozygous familial hypercholesterolemia is a rare disease usually caused by LDLR (low-density lipoprotein receptor) mutations. Homozygous familial hypercholesterolemia is characterized by markedly elevated LDL-C (low-density lipoprotein cholesterol) levels and an extremely high risk of premature atherosclerotic cardiovascular disease. A phase 2, proof-of-concept study (NCT02265952) demonstrated that evinacumab, a fully human monoclonal antibody to ANGPTL3 (angiopoietin-like 3 protein), reduced LDL-C levels in 9 patients with genotypically confirmed homozygous familial hypercholesterolemia and was well tolerated.

Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.

Aims: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.

Review of the long-term safety of lomitapide: a microsomal triglycerides transfer protein inhibitor for treating homozygous familial hypercholesterolemia.

Introduction: Homozygous familial hypercholesterolemia (HoFH) is a rare and life-threatening lipid disorder characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) concentrations and premature atherosclerotic cardiovascular disease (CVD). Conventional lipid-lowering agents remain insufficient in managing this disease, which emphasize the unmet medical need for potential therapies capable of lowering LDL-C and decreasing CVD risk in this patient population.

Areas Covered: Novel LDL receptor (LDLR) independent drugs have been recently approved or are in development for the treatment of HoFH, including lomitapide (Juxtapid®).

Association study between a polymorphic poly-T repeat sequence in the promoter of the somatostatin gene and metabolic syndrome.

Background: Metabolic syndrome is a cluster of factors associated with an increased risk of developing type 2 diabetes mellitus (T2D) and coronary artery disease (CAD). It is a complex disorder resulting from the interaction between various environmental factors and genetic susceptibility. The somatostatin (SST) gene has been shown to regulate a wide range of functions, particularly in energy homeostasis.

Efficacy of alirocumab in high cardiovascular risk populations with or without heterozygous familial hypercholesterolemia: Pooled analysis of eight ODYSSEY Phase 3 clinical program trials.

Objectives: Despite maximally tolerated statin therapy, many patients with high cardiovascular risk, with or without heterozygous familial hypercholesterolemia may require additional low-density lipoprotein cholesterol (LDL-C) reduction. We report pooled alirocumab (ALI) efficacy and safety data from eight Phase 3 trials in 4629 hypercholesterolemia patients, receiving background statin therapy.

Material And Methods: Studies were pooled by ALI dose and control: ALI 75/150mg every 2weeks (Q2W; dose increased to 150mg Q2W at Week 12 based on Week 8 LDL-C) versus ezetimibe (EZE; Pool 1) or placebo (PBO; Pool 2), and ALI 150mg Q2W versus PBO (Pool 3).

Novel therapies for severe dyslipidemia originating from human genetics.

Purpose Of Review: Novel therapies for severe dyslipidemia target a wide range of unmet medical needs: severe familial hypercholesterolemia, severe hypertriglyceridemia and chylomicronemia, elevated lipoprotein (a), lipodystrophies, high-density lipoprotein particle diseases, lysosomal acid lipase deficiency and storage diseases, nonalcoholic fatty liver disease and others. The purpose of this review is to describe the contribution of human genetics to the development of therapeutic approaches targeting severe dyslipidemia.

Recent Findings: Recent advances in human genetics and the identification of rare genetic variants having strong effects on disease risk not only accelerated the development of therapies for severe dyslipidemia, they also revealed new pathways, genes and mechanisms of health, disease or drug response, and facilitated molecular diagnosis, which may prove essential as the authorized use of some of these novel drugs is limited to specific conditions.