Evinacumab in homozygous familial hypercholesterolaemia: long-term safety and efficacy.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses the long-term safety and efficacy of evinacumab in adult and adolescent patients with HoFH. METHODS: In this open-label, single-arm, Phase 3 trial (NCT03409744), patients aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15 mg/kg every 4 weeks with stable lipid-lowering therapy. RESULTS: A total of 116 patients (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Patients were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively. CONCLUSIONS: In this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term.

Unexpected gaps in knowledge of familial hypercholesterolaemia among Dutch general practitioners.

BACKGROUND: Familial hypercholesterolaemia (FH) warrants early diagnosis to prevent premature atherosclerotic cardiovascular disease (CVD). However, underdiagnosis and undertreatment of FH persist. This study aimed to assess the knowledge and practice of FH care among general practitioners (GPs) in the Netherlands. METHODS: An internationally standardised, online questionnaire was sent to Dutch GPs between February 2021 and July 2022. The survey assessed knowledge and awareness of FH, encompassing general familiarity, awareness of management guidelines, inheritance, prevalence, CVD risk, and clinical practice related to FH. Comparative analysis was performed using data on primary care physicians from Western Australia, the Asia-Pacific region and the United Kingdom. RESULTS: Of the 221 participating GPs, 62.4% rated their familiarity with FH as above average (score > 4 on a 1-7 scale), with 91.4% considering themselves familiar with FH treatment and referral guidelines. Correct identification of the FH definition, typical lipid profile, inheritance pattern, prevalence and CVD risk was reported by 83.7%, 87.8%, 55.7%, 19.5%, and 13.6% of the respondents, respectively. Of the participants, 58.4% answered fewer than half of the 8 knowledge questions correctly. Dutch GPs reported greater FH familiarity and guideline awareness compared with their international counterparts but exhibited similar low performance on FH knowledge questions. CONCLUSION: Despite the Netherlands' relatively high FH detection rate, substantial knowledge gaps regarding FH persist among Dutch GPs, mirroring global trends. Enhanced FH education and awareness in primary care are imperative to improve FH detection and ensure adequate treatment. Targeting the global suboptimal understanding of FH might require international efforts.

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 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. RESULTS: The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups. CONCLUSIONS: In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.).

ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia-Brief Report.

[Figure: see text].

Taking One Step Back in Familial Hypercholesterolemia: STAP1 Does Not Alter Plasma LDL (Low-Density Lipoprotein) Cholesterol in Mice and Humans.

OBJECTIVE: STAP1, encoding for STAP1 (signal transducing adaptor family member 1), has been reported as a candidate gene associated with familial hypercholesterolemia. Unlike established familial hypercholesterolemia genes, expression of STAP1 is absent in liver but mainly observed in immune cells. In this study, we set out to validate STAP1 as a familial hypercholesterolemia gene. Approach and Results: A whole-body Stap1 knockout mouse model (Stap1-/-) was generated and characterized, without showing changes in plasma lipid levels compared with controls. In follow-up studies, bone marrow from Stap1-/- mice was transplanted to Ldlr-/- mice, which did not show significant changes in plasma lipid levels or atherosclerotic lesions. To functionally assess whether STAP1 expression in B cells can affect hepatic function, HepG2 cells were cocultured with peripheral blood mononuclear cells isolated from heterozygotes carriers of STAP1 variants and controls. The peripheral blood mononuclear cells from STAP1 variant carriers and controls showed similar LDLR mRNA and protein levels. Also, LDL (low-density lipoprotein) uptake by HepG2 cells did not differ upon coculturing with peripheral blood mononuclear cells isolated from either STAP1 variant carriers or controls. In addition, plasma lipid profiles of 39 carriers and 71 family controls showed no differences in plasma LDL cholesterol, HDL (high-density lipoprotein) cholesterol, triglycerides, and lipoprotein(a) levels. Similarly, B-cell populations did not differ in a group of 10 STAP1 variant carriers and 10 age- and sex-matched controls. Furthermore, recent data from the UK Biobank do not show association between STAP1 rare gene variants and LDL cholesterol. CONCLUSIONS: Our combined studies in mouse models and carriers of STAP1 variants indicate that STAP1 is not a familial hypercholesterolemia gene.

Advances, gaps and opportunities in the detection of familial hypercholesterolemia: overview of current and future screening and detection methods.

PURPOSE OF REVIEW: Studies reaffirm that familial hypercholesterolemia is more prevalent than initially considered, with a population frequency of approximately one in 300. The majority of patients remains unidentified. This warrants critical evaluation of existing screening methods and exploration of novel methods of detection. RECENT FINDINGS: New public policy recommendations on the detection of familial hypercholesterolemia have been made by a global community of experts and advocates. Phenotypic tools for diagnosing index cases remain inaccurate. Genetic testing is the gold standard for familial hypercholesterolemia and a new international position statement has been published. Correction of LDL cholesterol (LDL-C) for the cholesterol content of lipoprotein(a) [Lp(a)] may increase the precision of the phenotypic diagnosis of familial hypercholesterolemia. Cascade cotesting for familial hypercholesterolemia and elevated Lp(a) levels provides a new opportunity to stratify risk in families. Digital technology and machine learning methods, coupled with clinical alert and decision support systems, lead the way in more efficient approaches for detecting and managing index cases. Universal screening of children, combined with child-parent cascade testing, appears to be the most effective method for underpinning a population strategy for maximizing the detection of familial hypercholesterolemia. SUMMARY: Detection of familial hypercholesterolemia can be enhanced by optimizing current diagnostic algorithms, probing electronic health records with novel information technologies and integrating universal screening of children with cascade testing of parents and other relatives.

The next generation of triglyceride-lowering drugs: will reducing apolipoprotein C-III or angiopoietin like protein 3 reduce cardiovascular disease?

PURPOSE OF REVIEW: Apolipoprotein C-III (ApoC-III) and angiopoietin like protein 3 (angptl3) have emerged as key regulators of triglyceride metabolism. Based on Mendelian randomisation studies, novel therapeutic strategies inhibiting these proteins using monoclonal antibodies or gene silencing techniques might reduce residual cardiovascular disease (CVD) risk in dyslipidemic patients. This article aims to review the role of apoC-III and angptl3 in triglyceride metabolism and combine early clinical evidence of CVD reducing potential of these new therapeutic targets. RECENT FINDINGS: Angptl3 inhibition by mAb or antisense therapy has recently completed phase I and II studies, respectively and demonstrate robust apolipoprotein B (apoB) lowering up to 46%. Volanesorsen is an antisense therapy approved for patients with extremely elevated plasma triglyceride levels in which it showed no consistent apoB reduction. However, the GalNAc-conjugated oligonucleotide showed moderate (up to ∼30%) apoB reduction in a phase 1/2a dose-finding study. SUMMARY: Angptl3 and apoC-III are novel targets in lipoprotein metabolism that reduce triglycerides when inhibited. The expected CVD risk reduction may be mediated through reduced triglyceride-rich lipoprotein particle number, reflected by apoB, rather than triglyceride reduction per se. Limited human evidence shows that apoC-III and angptl3 inhibition both potently lower triglycerides, but since angptl3 inhibition reduces apoB more robustly it may be expected to confer more favorable CVD risk reduction.

Intranasal corticosteroids for non-allergic rhinitis.

BACKGROUND: Non-allergic rhinitis is defined as dysfunction and non-infectious inflammation of the nasal mucosa that is caused by provoking agents other than allergens or microbes. It is common, with an estimated prevalence of around 10% to 20%. Patients experience symptoms of nasal obstruction, anterior rhinorrhoea/post-nasal drip and sneezing. Several subgroups of non-allergic rhinitis can be distinguished, depending on the trigger responsible for symptoms; these include occupation, cigarette smoke, hormones, medication, food and age. On a cellular molecular level different disease mechanisms can also be identified. People with non-allergic rhinitis often lack an effective treatment as a result of poor understanding and lack of recognition of the underlying disease mechanism. Intranasal corticosteroids are one of the most common types of medication prescribed in patients with rhinitis or rhinosinusitis symptoms, including those with non-allergic rhinitis. However, it is unclear whether intranasal corticosteroids are truly effective in these patients. OBJECTIVES: To assess the effects of intranasal corticosteroids in the management of non-allergic rhinitis. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 7); PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 1 July 2019. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing intranasal corticosteroids, delivered by any means and in any volume, with (a) placebo/no intervention or (b) other active treatments in adults and children (aged ≥ 12 years). DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. The primary outcomes were patient-reported disease severity and a significant adverse effect - epistaxis. Secondary outcomes were (disease-specific) health-related quality of life, objective measurements of airflow and other adverse events. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 34 studies (4452 participants); however, only 13 studies provided data for our main comparison, intranasal corticosteroids versus placebo. The participants were mainly defined as patients with perennial rhinitis symptoms and negative allergy tests. No distinction between different pheno- and endotypes could be made, although a few studies only included a specific phenotype such as pregnancy rhinitis, vasomotor rhinitis, rhinitis medicamentosa or senile rhinitis. Most studies were conducted in a secondary or tertiary healthcare setting. No studies reported outcomes beyond three months follow-up. Intranasal corticosteroid dosage in the review ranged from 50 µg to 2000 µg daily. Intranasal corticosteroids versus placebo Thirteen studies (2045 participants) provided data for this comparison. These studies used different scoring systems for patient-reported disease severity, so we pooled the data in each analysis using the standardised mean difference (SMD). Intranasal corticosteroid treatment may improve patient-reported disease severity as measured by total nasal symptom score compared with placebo at up to four weeks (SMD -0.74, 95% confidence interval (CI) -1.15 to -0.33; 4 studies; 131 participants; I2 = 22%) (low-certainty evidence). However, between four weeks and three months the evidence is very uncertain (SMD -0.24, 95% CI -0.67 to 0.20; 3 studies; 85 participants; I2 = 0%) (very low-certainty evidence). Intranasal corticosteroid treatment may slightly improve patient-reported disease severity as measured by total nasal symptom score change from baseline when compared with placebo at up to four weeks (SMD -0.15, 95% CI -0.25 to -0.05; 4 studies; 1465 participants; I2 = 35%) (low-certainty evidence). All four studies evaluating the risk of epistaxis showed that there is probably a higher risk in the intranasal corticosteroids group (65 per 1000) compared to placebo (31 per 1000) (risk ratio (RR) 2.10, 95% CI 1.24 to 3.57; 4 studies; 1174 participants; I2 = 0%) (moderate-certainty evidence). The absolute risk difference (RD) was 0.04 with a number needed to treat for an additional harmful outcome (NNTH) of 25 (95% CI 16.7 to 100). Only one study reported numerical data for quality of life. It did report a higher quality of life score in the intranasal corticosteroids group (152.3 versus 145.6; SF-12v2 range 0 to 800); however, this disappeared at longer-term follow-up (148.4 versus 145.6) (low-certainty evidence). Only two studies provided data for the outcome objective measurements of airflow. These data could not be pooled because they used different methods of outcome measurement. Neither found a significant difference between the intranasal corticosteroids and placebo group (rhinomanometry SMD -0.46, 95% CI -1.06 to 0.14; 44 participants; peak expiratory flow rate SMD 0.78, 95% CI -0.47 to 2.03; 11 participants) (very low-certainty evidence). Intranasal corticosteroids probably resulted in little or no difference in the risk of other adverse events compared to placebo (RR 0.99, 95% CI 0.87 to 1.12; 3 studies; 1130 participants; I2 = 0%) (moderate-certainty evidence). Intranasal corticosteroids versus other treatments Only one or a few studies assessed each of the other comparisons (intranasal corticosteroids versus saline irrigation, intranasal antihistamine, capsaicin, cromoglycate sodium, ipratropium bromide, intranasal corticosteroids combined with intranasal antihistamine, intranasal corticosteroids combined with intranasal antihistamine and intranasal corticosteroids with saline compared to saline alone). It is therefore uncertain whether there are differences between intranasal corticosteroids and other active treatments for any of the outcomes reported. AUTHORS' CONCLUSIONS: Overall, the certainty of the evidence for most outcomes in this review was low or very low. It is unclear whether intranasal corticosteroids reduce patient-reported disease severity in non-allergic rhinitis patients compared with placebo when measured at up to three months. However, intranasal corticosteroids probably have a higher risk of the adverse effect epistaxis. There are very few studies comparing intranasal corticosteroids to other treatment modalities making it difficult to draw conclusions.

Transintestinal cholesterol excretion in humans.

PURPOSE OF REVIEW: To discuss recent insights into the measurement and cellular basis of transintestinal cholesterol excretion (TICE) in humans and to explore TICE as a therapeutic target for increasing reverse cholesterol transport. RECENT FINDINGS: TICE is the net effect of cholesterol excretion by the enterocyte into the intestinal lumen and is the balance between input and output fluxes through the enterocytes. These fluxes are: cholesterol excretion into the intestinal lumen mainly via ATP-binding cassette (ABC) G5/8, cholesterol absorption from the intestine by Niemann-Pick C1 like protein 1, the uptake of plasma lipoproteins by enterocytes at the basolateral membrane, and the excretion of cholesterol in chylomicrons into the lymph. Multiple studies have shown that TICE contributes to fecal neutral sterol (FNS) excretion in humans. TICE can be targeted with plant sterols, liver X receptor agonists, bile acids, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors. SUMMARY: TICE contributes significantly to FNS excretion in humans, independently of the biliary pathway. Knowledge about its underlying cellular mechanisms surges through in-vivo and in-vitro studies in mice and humans. TICE might be an interesting therapeutic target for increasing cholesterol disposal with the feces. Albeit multiple therapeutic options are available, studies showing clinical benefit are still needed.

Novel lipid modifying drugs to lower LDL cholesterol.

PURPOSE OF REVIEW: Statins have long been the cornerstone for the prevention of cardiovascular disease (CVD). However, because of perceived adverse effects and insufficient efficacy in certain groups of patients, considerable interest exists in the search for alternatives to lower LDL-cholesterol (LDL-C), and the recent approvals of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors underlines the success of this quest. Here, we give an updated overview on the most recent developments in the area of LDL-C lowering agents. RECENT FINDINGS: The clinical effects of the PCSK9 inhibitors are promising, especially now that the FOURIER and SPIRE programmes are published. Most cholesterylester-transfer protein inhibitors, however, except anacetrapib, have been discontinued because of either toxicity or lack of efficacy in large cardiovascular outcome trials. Other agents - like mipomersen, lomitapide, ETC-1002, and gemcabene - aim to lower LDL-C in different ways than solely through the LDL receptor, opening up possibilities for treating patients not responding to conventional therapies. New discoveries are also being made at the DNA and RNA level, with mipomersen being the first approved therapy based on RNA intervention in the United States for homozygous familial hypercholesterolemia. SUMMARY: Recent years have witnessed a new beginning for cholesterol-lowering compounds. With increased knowledge of lipid metabolism a score of new therapeutic targets has been identified. Mechanisms for modulation of those targets are also becoming more diverse while statins remain the backbone of CVD prevention, the new alternatives, such as PCSK9 monoclonals will probably play an important additional role in treatment of patients at risk for CVD.

Long-Term Efficacy and Tolerability of PCSK9 Targeted Therapy: A Review of the Literature.

Increased plasma levels of low-density lipoprotein cholesterol (LDL-C) are causally associated with atherosclerotic cardiovascular disease (ASCVD), and statins that lower LDL-C have been the cornerstone of ASCVD prevention for decades. However, guideline-recommended LDL-C targets are not achieved in about 60% of statin users. Proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeted therapy effectively lowers LDL-C levels and has been shown to reduce ASCVD risk. A growing body of scientific and clinical evidence shows that PCSK9-targeted therapy offers an excellent safety and tolerability profile with a low incidence of side effects in the short term. In this review, we present and discuss the current clinical and scientific evidence pertaining to the long-term efficacy and tolerability of PCSK9-targeted therapy.

Enhanced identification of familial hypercholesterolemia using central laboratory algorithms.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a highly prevalent genetic disorder resulting in markedly elevated LDL cholesterol levels and premature coronary artery disease. FH underdiagnosis and undertreatment require novel detection methods. This study evaluated the effectiveness of using an LDL cholesterol cut-off ≥99.5th percentile (sex- and age-adjusted) to identify clinical and genetic FH, and investigated underutilization of genetic testing and undertreatment in FH patients. METHODS: Individuals with at least one prior LDL cholesterol level ≥99.5th percentile were selected from a laboratory database containing lipid profiles of 590,067 individuals. The study comprised three phases: biochemical validation of hypercholesterolemia, clinical identification of FH, and genetic determination of FH. RESULTS: Of 5614 selected subjects, 2088 underwent lipid profile reassessment, of whom 1103 completed the questionnaire (mean age 64.2 ± 12.7 years, 48% male). In these 1103 subjects, mean LDL cholesterol was 4.0 ± 1.4 mmol/l and 722 (65%) received lipid-lowering therapy. FH clinical diagnostic criteria were met by 282 (26%) individuals, of whom 85% had not received guideline-recommended genetic testing and 97% failed to attain LDL cholesterol targets. Of 459 individuals consenting to genetic validation, 13% carried an FH-causing variant, which increased to 19% in clinically diagnosed FH patients. CONCLUSIONS: The identification of a substantial number of previously undiagnosed and un(der)treated clinical and genetic FH patients within a central laboratory database highlights the feasibility and clinical potential of this targeted screening strategy; both in identifying new FH patients and in improving treatment in this high-risk population.

Beyond early LDL cholesterol lowering to prevent coronary atherosclerosis in familial hypercholesterolaemia.

AIMS: Familial hypercholesterolaemia (FH) patients are subjected to a high lifetime exposure to low density lipoprotein cholesterol (LDL-C), despite use of lipid-lowering therapy (LLT). This study aimed to quantify the extent of subclinical atherosclerosis and to evaluate the association between lifetime cumulative LDL-C exposure and coronary atherosclerosis in young FH patients. METHODS AND RESULTS: Familial hypercholesterolaemia patients, divided into a subgroup of early treated (LLT initiated <25 years) and late treated (LLT initiated ≥25 years) patients, and an age- and sex-matched unaffected control group, underwent coronary CT angiography (CCTA) with artificial intelligence-guided analysis. Ninety genetically diagnosed FH patients and 45 unaffected volunteers (mean age 41 ± 3 years, 51 (38%) female) were included. Familial hypercholesterolaemia patients had higher cumulative LDL-C exposure (181 ± 54 vs. 105 ± 33 mmol/L ∗ years) and higher prevalence of coronary plaque compared with controls (46 [51%] vs. 10 [22%], OR 3.66 [95%CI 1.62-8.27]). Every 75 mmol/L ∗ years cumulative exposure to LDL-C was associated with a doubling in per cent atheroma volume (total plaque volume divided by total vessel volume). Early treated patients had a modestly lower cumulative LDL-C exposure compared with late treated FH patients (167 ± 41 vs. 194 ± 61 mmol/L ∗ years; P = 0.045), without significant difference in coronary atherosclerosis. Familial hypercholesterolaemia patients with above-median cumulative LDL-C exposure had significantly higher plaque prevalence (OR 3.62 [95%CI 1.62-8.27]; P = 0.001), compared with patients with below-median exposure. CONCLUSION: Lifetime exposure to LDL-C determines coronary plaque burden in FH, underlining the need of early as well as potent treatment initiation. Periodic CCTA may offer a unique opportunity to monitor coronary atherosclerosis and personalize treatment in FH.

This study reveals that young patients with familial hypercholesterolaemia (FH), as compared with individuals without FH, have a higher build-up of coronary artery plaque, linked directly to their increased lifetime exposure to LDL cholesterol. Genetically confirmed FH patients have a higher coronary plaque burden than those without FH, with every 75 mmol/L ∗ years increase in lifetime cumulative LDL cholesterol exposure resulting in a two-fold increase in total plaque volume. Early and potent LDL cholesterol lowering treatments are crucial for FH patients to prevent future cardiovascular diseases.

Use of Lipoprotein(a) to improve diagnosis and management in clinical familial hypercholesterolemia.

BACKGROUND AND AIMS: Lipoprotein(a) (Lp(a)) is an LDL-like particle whose plasma levels are largely genetically determined. The impact of measuring Lp(a) in patients with clinical familial hypercholesterolemia (FH) referred for genetic testing is largely unknown. We set out to evaluate the contribution of (genetically estimated) Lp(a) in a large nation-wide referral population of clinical FH. METHODS: In 1504 patients referred for FH genotyping, we used an LPA genetic instrument (rs10455872 and rs3798220) as a proxy for plasma Lp(a) levels. The genetic Lp(a) proxy was used to correct LDL-cholesterol and reclassify patients with clinical FH based on Dutch Lipid Criteria Network (DLCN) scoring. Finally, we used estimated Lp(a) levels to reclassify ASCVD risk using the SCORE and SMART risk scores. RESULTS: LPA SNPs were more prevalent among mutation-negative compared with mutation-positive patients (296/1280 (23.1%) vs 35/224 (15.6%), p = 0.016). Among patients with genetically defined high Lp(a) levels, 9% were reclassified to the DLCN category 'unlikely FH' using Lp(a)-corrected LDL-cholesterol (LDL-Ccor) and all but one of these patients indeed carried no FH variant. Furthermore, elevated Lp(a) reclassified predicted ASCVD risk into a higher category in up to 18% of patients. CONCLUSIONS: In patients referred for FH molecular testing, we show that taking into account (genetically estimated) Lp(a) levels not only results in reclassification of probability of genetic FH, but also has an impact on individual cardiovascular risk evaluation. However, to avoid missing the diagnosis of an FH variant, clear thresholds for the use of Lp(a)-cholesterol adjusted LDL-cholesterol levels in patients referred for genetic testing of FH must be established.

ANGPTL3 (Angiopoietin-Like 3) Preferentially Resides on High-Density Lipoprotein in the Human Circulation, Affecting Its Activity.

Background ANGPTL3 (angiopoietin-like protein 3) is an acknowledged crucial regulator of lipid metabolism by virtue of its inhibitory effect on lipoprotein lipase and endothelial lipase. It is currently unknown whether and to which lipoproteins ANGPTL3 is bound and whether the ability of ANGPTL3 to inhibit lipase activity is affected by binding to lipoproteins. Methods and Results Incubation of ultracentrifugation-isolated low-density lipoprotein (LDL) and high-density lipoprotein (HDL) fractions from healthy volunteers with recombinant ANGPTL3 revealed that ANGPTL3 associates with both HDL and LDL particles ex vivo. Plasma from healthy volunteers and a patient deficient in HDL was fractionated by fast protein liquid chromatography, and ANGPTL3 distribution among lipoprotein fractions was measured. In healthy volunteers, ≈75% of lipoprotein-associated ANGPTL3 resides in HDL fractions, whereas ANGPTL3 was largely bound to LDL in the patient deficient in HDL. ANGPTL3 activity was studied by measuring lipolysis and uptake of 3H-trioleate by brown adipocyte T37i cells. Unbound ANGPTL3 did not suppress lipase activity, but when given with HDL or LDL, ANGPTL3 suppressed lipase activity by 21.4±16.4% (P=0.03) and 25.4±8.2% (P=0.006), respectively. Finally, in a subset of the EPIC (European Prospective Investigation into Cancer) Norfolk study, plasma HDL cholesterol and amount of large HDL particles were both positively associated with plasma ANGPTL3 concentrations. Moreover, plasma ANGPTL3 concentrations showed a positive association with incident coronary artery disease (odds ratio, 1.25 [95% CI, 1.01-1.55], P=0.04). Conclusions Although ANGPTL3 preferentially resides on HDL, its activity was highest once bound to LDL particles.

Association Between Self-Rated Medication Adherence and Adverse Cardiovascular Outcomes in Patients With Hypertension.

Background Medication nonadherence contributes to poor health outcomes but remains challenging to identify. This study assessed the association between self-rated adherence and systolic blood pressure, low-density lipoprotein cholesterol levels, cardiovascular events, and all-cause mortality in SPRINT (Systolic Blood Pressure Intervention Trial). Methods and Results A total of 9361 patients randomized to 2 systolic blood pressure target groups, <120 mm Hg (intensive) and <140 mm Hg (standard), self-rated their medication adherence at each visit by marking a scale, ranging from 0% to 100%. Lower and high adherence were defined as scores ≤80% and >80%, respectively. Linear mixed effect regression models and Cox proportional hazard models were used to evaluate the association between self-rated adherence and systolic blood pressure and low-density lipoprotein cholesterol and cardiovascular events and all-cause mortality, respectively. A total of 9278 participants (mean age 68±9.4 years, 35.6% female) had repeated self-rated adherence measurements available, with a mean of 15±4 measurements per participant over 3.8 years follow-up. Of these, 2694 participants (29.0%) had ≥1 adherence measurements ≤80%. Compared with high-adherent patients, patients with lower adherence had significantly higher estimated on-treatment systolic blood pressure at 2-year follow-up: 128.7 (95% CI, 127.6-129.9) versus 120.0 (95% CI, 119.7-120.2) mm Hg in the intensive arm; and 139.8 (95% CI 138.4-141.1) versus 135.0 (95% CI 134.7-135.2) in the standard arm. Moreover, lower adherence was associated with an estimated 11 mg/dL higher low-density lipoprotein cholesterol level, more cardiovascular events (hazard ratio [HR], 1.69 [95% CI, 1.20-2.39]), and higher all-cause mortality (HR, 1.63 [95% CI, 1.16-2.31]). Conclusions Self-rated adherence allows identification of lower medication adherence and correlates with blood pressure control, low-density lipoprotein cholesterol levels, and adverse outcomes.

Concordance of a High Lipoprotein(a) Concentration Among Relatives.

Importance: Lipoprotein(a) (Lp[a]) concentrations are a highly heritable and potential causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent consensus statements by the European Atherosclerosis Society and American Heart Association recommend screening of relatives of individuals with high Lp(a) concentrations, but the expected yield of this approach has not been quantified in large populations. Objective: To measure the prevalence of high Lp(a) concentrations among first- and second-degree relatives of individuals with high Lp(a) concentrations compared with unrelated participants. Design, Setting, and Participants: In this cross-sectional analysis, pairs of first-degree (n = 19 899) and second-degree (n = 9715) relatives with measured Lp(a) levels from the UK Biobank study and random pairs of unrelated individuals (n = 184 764) were compared. Data for this study were collected from March 2006 to August 2010 and analyzed from December 2021 to August 2023. Exposure: Serum Lp(a) levels, with a high Lp(a) level defined as at least 125 nmol/L. Main Outcome and Measure: Concordance of clinically relevant high Lp(a) levels in first- and second-degree relatives of index participants with high Lp(a) levels. Results: A total of 52 418 participants were included in the analysis (mean [SD] age, 57.3 [8.0] years; 29 825 [56.9%] women). Levels of Lp(a) were correlated among pairs of first-degree (Spearman ρ = 0.45; P < .001) and second-degree (Spearman ρ = 0.22; P < .001) relatives. A total of 1607 of 3420 (47.0% [95% CI, 45.3%-48.7%]) first-degree and 514 of 1614 (31.8% [95% CI, 29.6%-34.2%]) second-degree relatives of index participants with high Lp(a) levels also had elevated concentrations compared with 4974 of 30 258 (16.4% [95% CI, 16.0%-16.9%]) pairs of unrelated individuals. The concordance in high Lp(a) levels was generally consistent among subgroups (eg, those with prior ASCVD, postmenopausal women, and statin users). The odds ratios for relatives to have high Lp(a) levels if their index relative had a high Lp(a) level compared with those whose index relatives did not have high Lp(a) levels were 7.4 (95% CI, 6.8-8.1) for first-degree relatives and 3.0 (95% CI, 2.7-3.4) for second-degree relatives. Conclusions and Relevance: The findings of this cross-sectional study suggest that the yield of cascade screening of first-degree relatives of individuals with high Lp(a) levels is over 40%. These findings support recent recommendations to use this approach to identify additional individuals at ASCVD risk based on Lp(a) concentrations.

Polygenic Background Modifies Risk of Coronary Artery Disease Among Individuals With Heterozygous Familial Hypercholesterolemia.

Background: Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder characterized by increased circulating low-density lipoprotein cholesterol and accelerated atherosclerosis. Even among this high-risk group, prior studies note considerable variability in risk of coronary artery disease (CAD). Objectives: The purpose of this study was to evaluate the cumulative impact of many common DNA variants-as quantified by a polygenic score-on incident CAD among individuals carrying a HeFH variant. Methods: We analyzed data from a prospective cohort study of 1,315 individuals who carried a HeFH variant and 1,315 matched family noncarriers derived from a nationwide screening program in the Netherlands, with subsequent replication in 151,009 participants of the UK Biobank. Results: Despite identification and lipid management within the Dutch screening program, 84 (6.4%) of HeFH variant carriers developed CAD as compared to 45 (3.4%) of matched family members (median follow-up 10.2 years, HR 1.88, 95% CI: 1.31-2.70). Among HeFH variant carriers, a polygenic score was associated with CAD with an effect size similar to low-density lipoprotein cholesterol - HR of 1.35 (95% CI: 1.07-1.70) and 1.41 (95% CI: 1.17-1.70) per standard deviation increase, respectively. When compared to noncarriers, CAD risk increased from 1.24-fold (95% CI: 0.64-2.34) to 3.37-fold (95% CI: 2.11-5.36) across quintiles of the polygenic score. A similar risk gradient, 1.36-fold (95% CI: 0.65-2.85) to 2.88-fold (95% CI: 1.59-5.20), was observed in 429 carriers in the UK Biobank. Conclusions: In 2 cohort studies involving 1,744 individuals with genetically confirmed HeFH - the largest study to date - risk of CAD varied according to polygenic background, in some cases approaching the risk observed in noncarriers.