Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder marked by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels from birth and a very high risk of premature atherosclerotic cardiovascular disease (ASCVD). To address the global paucity of observational data, the HoFH International Clinical Collaborators (HICC) registry (NCT04815005) was established. To date, over 950 HoFH individuals from 45 countries have been included. The median age at diagnosis was 12 years (IQR: 5.5-27.0), and untreated LDL-C levels were markedly elevated [median 14.7 mmol/L (11.6-18.4)]. At diagnosis, 9% had ASCVD or (supra)aortic valve disease, and despite the widespread use of lipid-lowering therapy (LLT), only 4% achieved guideline-recommended LDL-C goals. Early initiation of lipoprotein-apheresis was associated with greater LDL-C reductions and delayed ASCVD onset. Cardiovascular burden remains substantial, with a median age at death of 37 years [20-50]. No sex differences were observed in age or clinical characteristics at diagnosis, treatment patterns, or timing of ASCVD, although the usual sex gap in cardiovascular disease onset was absent. Profound global disparities persist, including limited genetic screening, restricted access to LLT, and earlier onset of major adverse cardiovascular events in non-high-income countries. Reproductive care for women remains highly variable and understudied. The HICC aims to guide global stakeholders in improving clinical outcomes for individuals with HoFH through earlier diagnosis, equitable access to advanced therapies, and broader inclusion of underserved regions. By generating evidence from routine clinical care and patient-reported data, identifying gaps in care, and fostering international collaboration, HICC seeks to advance a more equitable and effective global approach to HoFH management.

Cardiovascular screening has been shown to reduce mortality in trials involving men. This study evaluated the effect of cardiovascular screening in both sexes, with all-cause mortality as the primary outcome. The Viborg Screening Program, a prospective, population-based study in Denmark, in which the intervention consisted of inviting all 67-year olds to screening for carotid plaque, lower extremity artery disease, abdominal aortic aneurysm, hypertension, cardiac arrhythmia/ischaemia, and diabetes mellitus. This cohort included invitees from the first 5 years (2014-2019). Controls were 67-year olds without screening access. Effects were evaluated using propensity score matching (1:3 ratio, nearest-neighbour matching) and analysed using Cox proportional hazards models under the intention-to-invite principle. Sex-stratified analyses of all-cause mortality were conducted post hoc. Among 5505 invitees, three died before inclusion and 4602 participated (83.6%). Ninety individuals lacked registry information. After matching, 5412 invitees and 16 236 controls were included. During a median follow-up of 5.8 years, 372 (6.9%) invitees and 1444 (8.9%) controls died [hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.68-0.85; P < .001]. The number needed to invite to save one life was 49. The HR for cardiovascular mortality was 0.76 (95% CI 0.56-1.03), for major adverse cardiovascular events 1.10 (95% CI 1.01-1.19), and for major adverse limb events 0.70 (95% CI 0.50-0.98). All-cause mortality HRs were 0.73 (95% CI 0.63-0.84) for men, 0.82 (95% CI 0.68-0.98) for women, 0.70 (95% CI 0.61-0.80) for those without prior cardiovascular disease (CVD), and 0.97 (95% CI 0.78-1.21) for those with prior CVD. Multi-modality non-invasive cardiovascular screening reduced 5-year all-cause mortality among 67-year olds, also when stratified by sex. Prioritizing individuals without known CVD may enhance population-level impact.

Low-density lipoprotein cholesterol (LDL-C)-lowering therapies are proven effective in atherosclerotic cardiovascular disease (ASCVD), but real-world evidence for proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) monoclonal antibodies (mAb) remains limited. This study evaluated their impact in patients with ASCVD without prior ischaemic events. Patients initiating PCSK9i mAb from January 2016 to December 2022 were identified in the Optum Research Database. A 1:2 propensity score-matched comparator cohort of PCSK9i non-initiators was developed. The primary endpoint was a composite of non-fatal myocardial infarction, non-fatal ischaemic stroke, or all-cause mortality. Key outcomes from the parametric G-formula were 5-year event rates, relative risk reduction (RRR) and absolute risk reduction (ARR), with intention-to-treat (ITT) analysis. Additional outcomes for PCSK9i mAb initiators included absolute and percent LDL-C reduction from baseline. Overall, 19 670 patients met selection criteria (6545 PCSK9i mAb initiators; 13 125 non-initiators). Baseline characteristics were well-balanced. Under ITT, estimated 5-year event rates were 17.5% [95% confidence interval (CI) 15.5%, 19.5%] with PCSK9i mAb vs 25.4% (95% CI 23.6%, 27.1%) without PCSK9i, yielding a RRR of 30.9% and ARR of 7.8%. Individual endpoints showed RRRs of 28.3% for myocardial infarction (P < .0001), 26.4% for ischaemic stroke (P = .02), and 28.5% for all-cause mortality (P < .0001). Among initiators, mean baseline and follow-up LDL-C were 117.8 and 54.7 mg/dL (on-treatment analysis), respectively, representing an absolute reduction of 63.1 mg/dL and percent reduction of 53.6%. In ASCVD patients without prior events in clinical practice, PCSK9i mAb treatment was associated with lower ischaemic event and mortality rates.