BACKGROUND AND AIMS:Homozygous familial hypercholesterolemia (HoFH) is a rare disorder of lipid metabolism, characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels and marked premature cardiovascular disease. The Canadian HoFH Registry was established to understand treatment patterns and clinical outcomes for this population in Canada. This study aimed to investigate the clinical characteristics, use of lipid-lowering therapies, and cardiovascular outcomes of patients with HoFH. METHODS:The HoFH registry used a retrospective cohort study design to collect information on patients with a clinical or genetic diagnosis of HoFH. RESULTS:Data were available for 67 patients. At the last follow-up visit, the median age was 44 years (interquartile range (IQR): 25-61 years). The median age at diagnosis was 13 years (IQR 4-31 years) and the median highest recorded LDL-C level was 13.53 mmol/L (IQR 10.60-17.00 mmol/L). The lowest treated LDL-C levels were 1.80 mmol/L (IQR 0.92-3.00 mmol/L) with 86.6% of patients on statins, 85.1% on ezetimibe, 41.8% on PCSK9 inhibitors, 20.9% on lomitapide, 40.3% on evinacumab, and 43.3% treated with LDL apheresis/plasmapheresis. Major adverse cardiovascular events were observed in 20.9% of patients, with a mean age at onset of 41 years (IQR 20-53 years). CONCLUSIONS:This analysis provides valuable insights into the evolving clinical profile of patients with HoFH across Canada. Despite advances in treatment, a significant proportion of patients continue to experience major cardiovascular events, underscoring the need for early diagnosis, aggressive lipid-lowering management, and equitable access to evidence-based therapies to optimize long-term outcomes and improve survival in this population.

OBJECTIVE:Chylomicronemia is characterized by extreme hypertriglyceridemia (triglyceride values >10 mmol/L). It may be caused by a biallelic combination of a pathogenic variant [familial chylomicronemia syndrome (FCS)] or by genetic susceptibility combined with comorbidities and environmental factors [multifactorial chylomicronemia syndrome (MCS)]. Acute pancreatitis (AP) is the most serious complication of chylomicronemia. In the general population, the prevalence of AP during pregnancy is estimated to be <0.35%. As triglyceride levels significantly increase during pregnancy, it may affect the course of pregnancy and further increase the risk of AP in women with chylomicronemia. METHODS:One hundred sixteen pregnancies involving 49 European and North American women with a history of chylomicronemia (20 FCS, 29 MCS) were retrospectively reviewed. The occurrence of AP, the course of pregnancy, fetal development, and delivery were evaluated. RESULTS:Forty-two percent of FCS and 10% of MCS women experienced at least 1 AP episode during pregnancy (P = .01). Compared to MCS, women with FCS presented a higher percentage of pregnancies with AP (17% vs 5%, P = .02). Among all reviewed pregnancy-related AP, 56% occurred in primigravida FCS women compared to 0% in MCS. Premature deliveries were elevated in both groups, although they were more frequent in FCS (56%) vs MCS (19%) (P = .01). The percentages of miscarriages (11.8% vs 10.7%) and fetal failure to thrive (5.9% vs 9.2%) were not significantly different between the 2 cohorts. CONCLUSION:In this study, pregnant women with chylomicronemia had a 30-fold (MCS) to 120-fold (FCS) higher occurrence of AP compared to the general population. Chylomicronemia per se does not seem to influence fetal development.

BACKGROUND:Chylomicronemia is associated with extreme hypertriglyceridemia and an increased risk of acute pancreatitis and cardiometabolic complications. Rarely, chylomicronemia persists despite control of secondary causes and conventional treatments. The most severe form of persistent chylomicronemia (PC) is familial chylomicronemia syndrome (FCS). Diagnosis scoring systems have been developed to help clinicians differentiate FCS from other causes of chylomicronemia. OBJECTIVE:To assess the ability of FCS diagnosis scoring systems to discriminate FCS from other forms of PC. METHODS:This study included 413 Caucasians presenting a history of chylomicronemia, among whom 65 (15.7%) met the criteria of PC. The performance of 3 FCS diagnosis scoring systems (French Canadian, European, and North American) was evaluated. RESULTS:Among the 65 individuals with PC, 39 carried a biallelic combination of pathogenic variants (biallelic FCS). The 26 others were classified according to whether they presented a score above (clinical FCS) or below (multifactorial PC) the diagnosis threshold of FCS. Using the French Canadian system, 20/26 (76.9%) met FCS diagnosis criteria (clinical FCS) compared with 16/26 (61.5%) with the European system, 7/26 (26.9%) with the North American system at the threshold of 45 (FCS very likely), and 1 (3.8%) at the threshold of 60 (definite FCS). Among the 39 biallelic FCS, some scored below the clinical threshold of FCS. CONCLUSION:All diagnosis scoring systems, including the North American system at a threshold of 45, discriminate multifactorial PC from biallelic FCS and fairly identify people presenting characteristics of FCS without having the capacity of distinguishing biallelic FCS from clinical FCS. FCS clinical diagnosis systems might contribute to equitable access to precision medicine for patients affected by PC.

Background Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease of low-density lipoprotein cholesterol (LDL-C) metabolism. This disease is associated with a major risk of both atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis (AS). The predictors of AS in this population are not well established. Objective To investigate the univariable and multivariable predictors of AS in patients from the Canadian HoFH Registry. Methods Individuals from the Canadian HoFH Registry were included in this retrospective longitudinal study. Clinical data were obtained from the treating physicians using a standardized questionnaire. Cox proportional hazards models were used to investigate the predictors of AS. The observed lifetime risk of AS was calculated using Kaplan-Meier estimates. Results Among the 67 patients with HoFH, 25 (37 %) developed AS. The mean age at baseline was 22 ± 17 years and women represented 57% of the cohort. The independent predictors of AS were the baseline LDL-C (HR 1.22 [1.09-1.35], p=0.0003) as well as the presence of at least one null genetic variant (HR 3.73 [1.41-9.86], p=0.008). Having a baseline LDL-C value above 13 mmol/L was associated with an observed lifelong risk of developing AS approaching 100% within this cohort, whereas having a value below this threshold was associated with a risk of 27% (p=0.0002). Conclusion This is the first systematic evaluation within a national HoFH registry to report the univariable and multivariable predictors of AS in patients with HoFH. An external validation of our results in an international cohort of HoFH is warranted.

Lipoprotein(a) [Lp(a)] is an independent, heritable risk factor for atherosclerotic cardiovascular disease. Guidelines recommend Lp(a) testing once in a lifetime and recognize it as a risk-enhancing factor. However, management of elevated Lp(a) in real-world clinical practice is not well described. Here we describe the rationale, design, and preliminary baseline characteristics of the Canadian Lp(a) Registry, a prospective, longitudinal observational study of patients with Lp(a) ≥ 100 nmol/L (≥ 50 mg/dL). Patient demographics, cardiovascular risk factors, laboratory results, and clinical outcomes are collected at baseline and at annual follow-up. The primary objective is to evaluate the clinical management and outcomes of patients with elevated Lp(a). From April 2024 to April 2025, 127 patients (mean age 57.5 ± 12.7 years, 48.8% female) were enrolled with a median Lp(a) level of 225 nmol/L (interquartile range 186-346 nmol/L), and 51.2% had multiple Lp(a) levels obtained. The most recent mean low-density lipoprotein cholesterol (LDL-C) was 2.49 ± 1.74 mmol/L. At the time of registry entry, 104 (81.9%) patients were receiving lipid-lowering therapies, including statins (74.8%), ezetimibe (48.0%), and proprotein convertase subtilisin/kexin type 9 inhibitors (27.6%), whereas 18.1% were not taking prescription lipid-lowering therapy. There were 66 (52.0%) patients with an LDL-C < 2.0 mmol/L. The Canadian Lp(a) Registry is an ongoing prospective, observational study designed to evaluate the clinical management, cardiovascular risk profile, and outcomes for patients with elevated Lp(a). It is expected to improve our understanding of how elevated Lp(a) is managed in contemporary clinical practice and to identify opportunities to improve care.

BACKGROUND:Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extreme elevations in low-density lipoprotein cholesterol levels and premature cardiovascular disease. OBJECTIVES:The objective of this study was to assess the prevalence, clinical presentation, and current therapeutic approaches for aortic stenosis in Canadian patients with HoFH. METHODS:Demographic data, lipid profiles, and genetic testing results for patients with HoFH were collected prospectively since 2008. Reports from echocardiography, cardiac catheterization, and surgical or transcatheter interventions involving the aortic valve and/or ascending aorta were retrieved from medical records. RESULTS:Data were available for 63 patients with either a clinical diagnosis (n = 14, 22.2%) or genetic confirmation (n = 49, 77.8%) of HoFH. The median age at diagnosis was 14.0 years (Q1-Q3: 6.0 to 31.0), the median highest recorded low-density lipoprotein cholesterol level was 13.0 mmol/L (Q1-Q3: 10.6-16.3), and 17 patients (27.0%) developed moderate-to-severe aortic stenosis. Extensive calcification of the aortic valve and ascending aorta, combined with severe valvular and/or supravalvular stenosis and coronary ostial stenosis, necessitated complex and often consecutive surgical procedures. Six transcatheter aortic valve replacements were performed in 4 patients, 4 of which failed. Thirteen patients (20.6%) underwent at least 1 surgical aortic valve procedure. Patients developed aortic stenosis at a young age despite intensive treatment, including lipoprotein apheresis started at an early age. CONCLUSIONS:Moderate-to-severe aortic stenosis was observed in 27.0% of patients in the Canadian HoFH Registry, with 20.6% requiring invasive intervention. The severe aortic phenotype associated with HoFH requires complex, multidisciplinary surgical management in specialized centers with appropriate expertise.

BACKGROUND:Inclisiran, a small interfering RNA targeting hepatic PCSK9, was previously studied in various adult patient populations, but it has not yet been assessed in paediatric patients with heterozygous familial hypercholesterolaemia (HeFH), a genetic disorder characterised by elevated LDL cholesterol. The ORION-16 study aimed to evaluate the efficacy and safety of inclisiran treatment in adolescents with HeFH. METHODS:ORION-16 was a two-part (1-year double-blind, 1-year open-label), randomised, phase 3 trial at 51 sites across 26 countries. In Part 1, adolescents (aged 12 to <18 years) with HeFH and elevated LDL cholesterol on maximally tolerated statin treatment with or without other lipid-lowering therapy were randomly assigned 2:1 (via interactive response technology) to either inclisiran sodium 300 mg subcutaneously or placebo (administered on days 1, 90, and 270); in Part 2, all patients received inclisiran (days 360 [only patients previously assigned to receive placebo], 450, and 630). The primary endpoint was the percentage change in LDL cholesterol from baseline to day 330, assessed in all randomly assigned patients. Safety was assessed in all patients who received at least one dose of study drug. Endpoints in Part 2 were analysed in all patients who entered and received at least one dose of study drug in Part 2. ORION-16 is registered at ClinicalTrials.gov (NCT04652726) and is completed. FINDINGS:Between Feb 17, 2021, and Dec 14, 2022, 141 patients were randomly assigned (93 to inclisiran, 48 to placebo; median age 15·1 years [IQR 13·4-16·8]; 75 [53%] female; 128 [91%] White). In Part 1, the least squares mean percentage change in LDL cholesterol from baseline to day 330 was -27·1% in the inclisiran group and 1·4% in the placebo group, with a between-group difference of -28·5% (95% CI -35·8 to -21·3; p<0·0001). In Part 2, at day 720, a mean percentage change in LDL cholesterol from baseline of -33·7% (SD 24·0) was observed. Inclisiran was well tolerated, with a safety profile comparable to studies in adults. Injection site reactions were more frequent with inclisiran (15 [16%] of 93 patients) than with placebo (three [6%] of 48) in Part 1 (13 [9%] of 139 in Part 2); all were mild and did not lead to study drug discontinuation. There were no treatment-related serious adverse events, and no deaths during the study. INTERPRETATION:In adolescents with HeFH, inclisiran was effective in lowering LDL cholesterol, with sustained efficacy over 2 years, and was well tolerated. These results support inclisiran as a potentially useful addition for the treatment of adolescents with HeFH, providing an infrequent dosing regimen. FUNDING:Novartis Pharma.

BACKGROUND:ANGPTL3 plays a key part in lipoprotein metabolism. Zodasiran, a liver-targeted RNA interference therapeutic, inhibits ANGPTL3 expression and reduces atherogenic lipoproteins through mechanisms independent of the LDL receptor (LDLR). This approach is relevant to patients with homozygous familial hypercholesterolaemia (HoFH) who have extreme elevations of LDL cholesterol due to markedly impaired LDLR function and, as a result, very high risk of premature adverse cardiovascular events. We aimed to evaluate the long-term safety and efficacy of zodasiran in patients with HoFH. METHODS:GATEWAY was an open-label, randomised, phase 2 study done at seven clinical sites in Australia, Canada, South Africa, and the USA. Patients aged 16 years or older with documented HoFH who were receiving stable lipid-lowering therapy, were on a low-fat diet, had a screening LDL cholesterol of 2·6 mmol/L (100 mg/dL) or higher, and had triglycerides less than 3·4 mmol/L (300 mg/dL) were randomly assigned (1:1) using a block design to receive subcutaneous injections of 200 mg or 300 mg zodasiran on day 1 and month 3. When a majority of patients completed 6 months of treatment, an interim, non-binding, aggregate analysis of efficacy and safety data was conducted according to an adaptive study design to decide whether a single dose could be used for longer-term evaluation. After 9 months of follow-up, patients could opt for long-term open-label extension for an additional 24 months of subcutaneous zodasiran 200 mg injections every 3 months, as established following the planned interim analysis. The primary endpoint was percentage change from baseline to month 6 in fasting LDL cholesterol and was assessed in all randomly assigned patients who received at least one dose of study drug. Safety was assessed in all patients who received one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05217667, and is ongoing (recruitment has now ended). FINDINGS:Between April 1 and Nov 12, 2022, 18 patients (mean age 43·0 years [SD 19·4] and 14 [78%] White) were randomly assigned to receive zodasiran 200 mg (n=9) or 300 mg (n=9). Mean baseline LDL cholesterol concentration was 9·8 mmol/L (SD 5·7) despite background lipid-lowering therapy. At month 6, patients showed substantial dose-responsive reductions in fasting LDL cholesterol (mean -35·7% [SD 28·6; 95% CI -57·6 to -13·7] with 200 mg and -39·9% [18·1; -53·9 to -26·0]) with 300 mg, which was consistent with the interim results of more than 40% reduction in both groups. Following partial washout, all patients entered the open-label extension, in which zodasiran showed evidence of continued effect, with reductions in fasting LDL cholesterol (mean -40·7% [SD 22·3] for the pooled doses) observed for an additional 12 months, as the study was stopped early for business reasons. Reductions were greater in a subset of patients in whom lipid-lowering therapy included a PCSK9 inhibitor (mean -55·8% [SD 19·1] at month 6 of the randomised treatment period and -51·9% [11·6] at month 12 of the open-label extension). There were no drug discontinuations, drug-related severe adverse events, or deaths. In the randomised treatment period, treatment-emergent adverse events occurred in six (67%) of nine patients in the zodasiran 200 mg group and six (67%) of nine patients in the zodasiran 300 mg group, with the most frequent adverse events being nasopharyngitis (two [22%] vs two [22%]), dizziness (two [22%] vs one [11%]), and upper respiratory tract infections (one [11%] vs one [11%]). Adverse events occurred in 11 (61%) of 18 patients in the open-label extension, and the most frequent adverse events were COVID-19 (five [28%]) and nasopharyngitis (five [28%]). INTERPRETATION:Quarterly dosed zodasiran shows evidence of reductions in LDL cholesterol with a favourable safety profile, in patients with HoFH receiving background lipid-lowering therapy. Further investigation in phase 3 trials is warranted. FUNDING:Arrowhead Pharmaceuticals.

BACKGROUND:Familial chylomicronemia syndrome (FCS), a rare genetic disorder, markedly increases plasma triglycerides and the risk of acute pancreatitis. FCS symptoms can profoundly impact patients' quality of life. OBJECTIVE:To explore the FCS patient experience during olezarsen treatment, including perceptions of meaningful changes in FCS symptoms and impacts. METHODS:Patients with FCS continuing olezarsen treatment in an open-label extension (OLE) (NCT05130450) of the randomized, placebo-controlled phase 3 Balance study (NCT04568434) participated in 1-hour qualitative interviews. Thematic analysis was conducted. RESULTS:Among 18 OLE participants who completed interviews (55.6% female; mean age, 43.5 years), 17 reported a history of pancreatitis, including 14 with pancreatitis events within 10 years prior to enrollment in the Balance study (13/14 requiring hospitalization). All participants reported having experienced FCS-related symptoms before trial enrollment (most commonly, abdominal pain [94.4%], physical fatigue [66.7%], diarrhea [55.6%], vomiting [50.0%], nausea [33.3%], and difficulty thinking [27.8%]) and impacts (most commonly, dietary restrictions [100%], mood/emotions [94.4%], hospitalizations [77.8%], and social activities [77.8%]). Fifteen of 18 participants (83.3%) reported improvements with olezarsen treatment, including reductions in FCS-related symptoms (abdominal pain [n = 14/17; 82.4%], physical fatigue [n = 7/12; 58.3%], diarrhea [n = 6/10; 60.0%], vomiting [n = 7/8; 87.5%], nausea [n = 3/5; 60.0%], and difficulty thinking [n = 3/5; 60.0%]) and impacts (relationships [n = 6/7; 85.7.0%], hospital admittances [n = 11/14; 78.6%], finances [n = 3/4; 75.0%], and mood/emotions [n = 12/17; 70.6%]). Most participants (15/18; 83.3%) reported meaningful improvements and indicated they were satisfied with olezarsen treatment. CONCLUSION:Results of this qualitative study underscore the significant burden of FCS and support the effectiveness of olezarsen from the patient perspective.

Funding This study was sponsored by Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. Medical writing and editorial support were provided by Elisabetta Lauretti, PhD, of Red Nucleus, and funded by Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. Background/Synopsis Familial chylomicronemia syndrome (FCS) is a rare genetic disorder of deficient lipolytic capacity causing severe hypertriglyceridemia and increased acute pancreatitis risk. Olezarsen is a triantennary N-acetyl galactosamine–conjugated antisense oligonucleotide that targets hepatic APOC3 mRNA for degradation. In Balance (NCT04568434), a phase 3 study in patients with genetically-identified FCS, olezarsen 80 mg vs placebo significantly reduced triglycerides and was associated with reduced acute pancreatitis events. Olezarsen 80 mg is approved in United States as an adjunct to diet to reduce triglycerides in adults with FCS. In clinical laboratories, genetic testing results for FCS are reported as “positive” (or “pathogenic/likely pathogenic”) “indeterminate” or “negative.” However, publicly available databases may be incomplete or not up to date for all potentially pathogenic variants. Objective/Purpose This post hoc analysis from Balance examined the prevalence, baseline characteristics, and reclassification of initially indeterminate genetic test results in patients with suspected FCS. Methods After eligibility assessment and screening for enrollment in Balance, genetic testing was performed by a commercial laboratory (Prevention Genetics, Marshfield, WI). Prior to randomization, initial laboratory results were further adjudicated by a core laboratory (Western University, London, ON, Canada) using independent bioinformatics and non-public research registry data. Results Of 131 patients tested, 67 (51%) were initially designated positive, 10 (8%) negative, and 54 (41%) indeterminate for FCS, the latter because of “variants of uncertain significance” (VUSs). Compared with positive patients, initially indeterminate patients were more likely to be male, non-White, have a lower prevalence of pancreatitis, and have a lower value for chylomicron-triglycerides and higher values for ApolipoproteinC-III (ApoC-III), low-density lipoprotein-C (LDL-C), and apolipoprotein B (apoB) (Table 1). All initially positive and negative patients were adjudicated as such by the core laboratory. However, indeterminate laboratory results were subsequently reclassified as pathogenic/likely pathogenic in 15/54 (28%) patients and as negative in 39/54 (72%). Over 53 weeks, 7 initially positive (13%; 1 olezarsen 80 mg, 1 olezarsen 50 mg, 5 placebo) and 2 initially indeterminate patients (17%; both placebo) had adjudicated acute pancreatitis episodes. Conclusions Of patients with suspected FCS initially reported as indeterminate, a substantial proportion (28%) had genetically-confirmed FCS using a more comprehensive assessment. In patients with indeterminate genetic results, pending refinement of genetic testing, consideration should be given for using clinical risk scores to diagnose FCS. A global curated public database of FCS-related DNA variants in racially diverse populations may allow more accurate classification of pathogenic FCS variants.

BACKGROUND AND AIMS:Children and adolescents with homozygous familial hypercholesterolemia (HoFH) routinely require advanced lipid-lowering therapies (LLTs). We assess the long-term efficacy and safety of evinacumab, a novel LLT, in children and adolescents with HoFH. METHODS:Study 17100 (NCT04233918) was a phase 3, single-arm, open-label study enrolling 20 children aged 5-11 years with HoFH. ELIPSE-OLE (NCT03409744) was a phase 3, single-arm study enrolling 14 adolescents aged 12-17 years with HoFH. Participants received intravenous evinacumab 15 mg/kg every 4 weeks; all individuals received stable LLT and most received lipoprotein apheresis (60 % of children aged 5-11 years; 64 % of adolescents aged 12-17 years). Outcomes included change from baseline to weeks 48 and 72 in low-density lipoprotein cholesterol (LDL-C) and other lipid parameters. Safety was assessed as treatment-emergent adverse events (TEAEs). RESULTS:In children aged 5-11 years, mean (standard deviation [SD]) baseline LDL-C (301.9 [149.1] mg/dL) was lowered by 45 % (131.1 mg/dL) at week 48 and 41 % (115.8 mg/dL) at week 72. In adolescents aged 12-17 years, mean (SD) baseline LDL-C (300.4 [100.5] mg/dL) was lowered by 48 % (156.4 mg/dL) at week 48 and 51 % (165.6 mg/dL) at week 72. TEAEs occurred in 100 % and 86 % of participants aged 5-11 and 12-17 years, respectively. TEAEs were considered treatment related in four individuals aged 5-11 years (20 %); no one aged 12-17 years had treatment-related TEAEs (0 %). CONCLUSIONS:Evinacumab markedly reduced LDL-C in children and adolescents with HoFH, beyond optimized standard LLT and lipoprotein apheresis. LDL-C remains above goal in most pediatric patients with HoFH, and evinacumab should be routinely considered whenever further LDL-C lowering is needed.

BACKGROUND:Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease of low-density lipoprotein cholesterol (LDL-C) metabolism. Despite the devastating effect of this disease on atherosclerotic cardiovascular health, the disease phenotype and severity are more heterogeneous than previously thought. The predictors of atherosclerotic cardiovascular disease (ASCVD) in HoFH patients have never been systematically studied. OBJECTIVE:To investigate the univariate and multivariate predictors of ASCVD in HoFH patients. METHODS:Patients from the Canadian HoFH Registry were included in the present retrospective longitudinal study. Data for these patients were collected using a standardized questionnaire between 2019 and 2022 in 19 academic sites across Canada. Predictors of ASCVD were evaluated using Cox proportional hazards models. RESULTS:Among 48 HoFH patients, 26 (54%) of them had at least 1 ASCVD event. The average age at baseline was 19 ± 15 years and women represented 56% of the cohort. The independent predictors of ASCVD events were male sex (HR 2.57 [1.13-5.84]), diabetes (HR 16.22 [3.38-77.97]), and LDL-C above the median of 14.45 mmol/L (559 mg/dL) (HR 3.10 [1.24-7.76]). When performing subgroup analysis according to sex, the presence of LDL-C above the median was associated with a significantly higher probability of ASCVD (88% vs 43%, P = .005) in women, but not in men (100% at age 40 in both groups, P = .98). CONCLUSION:This study reported for the first time the univariate and multivariate predictors of ASCVD in HoFH patients. We demonstrate that predictors of ASCVD in HoFH differ in males and females with respect to LDL-C levels.

AIMS:PCSK9 inhibition intensively lowers low density lipoprotein cholesterol and is well tolerated in adults and paediatric patients with familial hypercholesterolaemia (FH). HAUSER-RCT showed that 24 weeks of treatment with evolocumab in paediatric patients did not affect cognitive function. This study determined the effects of 80 additional weeks of evolocumab treatment on cognitive function in paediatric patients with heterozygous FH. METHODS AND RESULTS:HAUSER-OLE was an 80-week open-label extension of HAUSER-RCT, a randomized, double-blind, 24-week trial evaluating the efficacy and safety of evolocumab in paediatric patients (ages 10-17 years) with FH. During the OLE, all patients received monthly 420 mg subcutaneous evolocumab injections. Tests of psychomotor function, attention, visual learning, and executive function were administered at baseline and Weeks 24 and 80 of the OLE. Changes over time were analysed descriptively and using analysis of covariance. Cohen's d statistic was used to evaluate the magnitude of treatment effects. Analysis of covariance results indicated no decrease in performance across visits during 80 weeks of evolocumab treatment for Groton Maze Learning, One Card Learning accuracy, Identification speed, or Detection speed (all P > 0.05). Performance on all tasks was similar for those who received placebo or evolocumab in the RCT (all P > 0.05). For all tests, the least square mean differences between patients who received placebo vs. evolocumab in the parent study were trivial (all Cohen's d magnitude < 0.2). CONCLUSION:In paediatric patients with FH, 80 weeks of open-label evolocumab treatment had no negative impact on cognitive function. REGISTRATION:ClinicalTrials.gov identifier: NCT02624869.

BACKGROUND: Statins are the leading lipid -lowering drugs, reducing blood cholesterol by controlling its synthesis. Side effects are linked to the use of statins, in particular statin-associated muscle symptoms (SAMS). Some data suggest that vitamin D supplementation could reduce SAMS. OBJECTIVE: The purpose of this study was to evaluate the potential benefits of vitamin D supplementation in a randomized controlled trial. METHODS: Men ( n = 23) and women ( n = 15) (50.5 +/- 7.7 years [mean +/- SD]) in primary cardiovascular prevention, self -reporting or not SAMS, were recruited. Following 2 months of statin withdrawal, patients were randomized to supplementation (vitamin D or placebo). After 1 month of supplementation, statins were reintroduced. Before and 2 months after drug reintroduction, muscle damage (creatine kinase and myoglobin) was measured. Force (F), endurance (E) and power (P) of the leg extensors ( ExT ) and flexors ( fLE ) and handgrip strength (FHG) were also measured with isokinetic and handheld dynamometers, respectively. The Short Form 36 Health Survey (SF -36) questionnaire and a visual analog scale (VAS) were administrated to assess participants' self -reported health -related quality of life and SAMS intensity, respectively. Repeated -measures analysis was used to investigate the effects of time, supplementation, and their interaction, according to the presence of SAMS. RESULTS: Despite no change for objective measures, subjective measures worsened after reintroduction of statins, independent of supplementation (VAS, SF -36 mental component score, all p < 0.05). However, no interaction between time and supplementation according to the presence of SAMS was observed for any variables. CONCLUSIONS: Vitamin D supplementation does not appear to mitigate SAMS. (c) 2023 National Lipid Association. Published by Elsevier Inc. All rights reserved.

[This corrects the article DOI: 10.31083/j.rcm2505190.].