Stephen J. Nicholls

Background: Elevated lipoprotein(a) concentrations are associated with atherosclerotic cardiovascular disease. The safety and efficacy of lepodisiran, an extended-duration, small interfering RNA targeting hepatic synthesis of lipoprotein(a), are unknown. Methods: We randomly assigned participants in a 1:2:2:2:2 ratio to receive lepodisiran at a dose of 16 mg, 96 mg, or 400 mg at baseline and again at day 180, lepodisiran at a dose of 400 mg at baseline and placebo at day 180, or placebo at baseline and at day 180, all administered by subcutaneous injection. Data from the two groups that received lepodisiran at a dose of 400 mg at baseline were pooled for the primary analysis. The primary end point was the time-averaged percent change from baseline in the serum lipoprotein(a) concentration (lepodisiran difference from placebo [i.e., placebo-adjusted]) during the period from day 60 to day 180. Results: A total of 320 participants underwent randomization; the median baseline lipoprotein(a) concentration was 253.9 nmol per liter. The placebo-adjusted time-averaged percent change from baseline in the serum lipoprotein(a) concentration from day 60 to day 180 was -40.8 percentage points (95% confidence interval [CI], -55.8 to -20.6) in the 16-mg lepodisiran group, -75.2 percentage points (95% CI, -80.4 to -68.5) in the 96-mg group, and -93.9 percentage points (95% CI, -95.1 to -92.5) in the pooled 400-mg groups. The corresponding change from day 30 to day 360 was -41.2 percentage points (95% CI, -55.4 to -22.4), -77.2 percentage points (95% CI, -81.8 to -71.5), -88.5 percentage points (95% CI, -90.8 to -85.6), and -94.8 percentage points (95% CI, -95.9 to -93.4) in the 16-mg, 96-mg, 400-mg-placebo, and 400-mg-400-mg dose groups, respectively. Serious adverse events, none of which were deemed by investigators to be related to lepodisiran or placebo, occurred in 35 participants. Dose-dependent, generally mild injection-site reactions occurred in up to 12% (8 of 69) of the participants in the highest lepodisiran dose group. Conclusions: Lepodisiran reduced mean serum concentrations of lipoprotein(a) from 60 to 180 days after administration. (Funded by Eli Lilly; ALPACA ClinicalTrials.gov number, NCT05565742.).

Background: Obicetrapib is a highly selective cholesteryl ester transfer protein inhibitor that reduces low-density lipoprotein (LDL) cholesterol levels. The efficacy and safety of obicetrapib have not been fully characterized among patients at high risk for cardiovascular events. Methods: We conducted a multinational, randomized, placebo-controlled trial involving patients with heterozygous familial hypercholesterolemia or a history of atherosclerotic cardiovascular disease who were receiving maximum tolerated doses of lipid-lowering therapy. Patients with an LDL cholesterol level of 100 mg per deciliter or higher or a non-high-density lipoprotein (HDL) cholesterol level of 130 mg per deciliter or higher, as well as those with an LDL cholesterol level of 55 to 100 mg per deciliter or a non-HDL cholesterol level of 85 to 130 mg per deciliter and at least one additional cardiovascular risk factor, were eligible for inclusion. The patients were randomly assigned in a 2:1 ratio to receive either 10 mg of obicetrapib once daily or matching placebo for 365 days. The primary end point was the percent change in the LDL cholesterol level from baseline to day 84. Results: A total of 2530 patients underwent randomization; 1686 patients were assigned to receive obicetrapib and 844 to receive placebo. The mean age of the patients was 65 years, 34% were women, and the mean baseline LDL cholesterol level was 98 mg per deciliter. The least-squares mean percent change from baseline to day 84 in the LDL cholesterol level was -29.9% (95% confidence interval [CI], -32.1 to -27.8) in the obicetrapib group, as compared with 2.7% (95% CI, -0.4 to 5.8) in the placebo group, for a between-group difference of -32.6 percentage points (95% CI, -35.8 to -29.5; P<0.001). The incidence of adverse events appeared to be similar in the two groups. Conclusions: Among patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia who were receiving maximum tolerated doses of lipid-lowering therapy and were at high risk for cardiovascular events, obicetrapib reduced LDL cholesterol levels by 29.9%. (Funded by NewAmsterdam Pharma; BROADWAY ClinicalTrials.gov number, NCT05142722.).

There is striking evidence that a high lipoprotein(a) [Lp(a)] concentration is a strong, independent, and causal cardiovascular risk factor. However, Lp(a) testing rates are very low (1 %-2 %) despite the fact that 1 in 5 individuals have elevated Lp(a) concentrations. The Brussels International Declaration on Lp(a) Testing and Management was co-created by the Lp(a) International Task Force and global leaders at the Lp(a) Global Summit, held in Brussels, Belgium, on March 24-25, 2025. The event, organized by FH Europe Foundation, brought together scientific experts, people with the lived experience of elevated Lp(a) and policy makers from the European Institutions and World Health Organization. The World Heart Federation, Global Heart Hub, and European Alliance for Cardiovascular Health and scientific organizations such as European Atherosclerosis Society, and International Atherosclerosis Society were formal partners. The Summit was hosted by a Member of the European Parliament, Romana Jerković, and held under the patronage of the Polish presidency of the Council of the European Union. The Declaration calls for 1) integration of Lp(a) testing and management into Global, European and National Cardiovascular Health Plans; 2) appropriate investment, policy and programmes in targeting Lp(a) testing and management based on a recent study demonstrating the substantial overall cost-saving to health systems across the globe; 3) political commitment to mandate systematic Lp(a) testing at least once during a person's lifetime, ideally at an early age, with full reimbursement; 4) incorporation of Lp(a) test results in the context of a person's cardiovascular risk assessment, with development of personalised cardiovascular health roadmaps as needed, without fear of discrimination; 5) investment in public and healthcare professional education to increase awareness of Lp(a) and its impact on cardiovascular health.

There is striking evidence that a high lipoprotein(a) [Lp(a)] concentration is a strong, independent, and causal cardiovascular risk factor. However, Lp(a) testing rates are very low (1 %-2 %) despite the fact that 1 in 5 individuals have elevated Lp(a) concentrations. The Brussels International Declaration on Lp(a) Testing and Management was co-created by the Lp(a) International Task Force and global leaders at the Lp(a) Global Summit, held in Brussels, Belgium, on March 24-25, 2025. The event, organized by FH Europe Foundation, brought together scientific experts, people with the lived experience of elevated Lp(a) and policy makers from the European Institutions and World Health Organization. The World Heart Federation, Global Heart Hub, and European Alliance for Cardiovascular Health and scientific organizations such as European Atherosclerosis Society, and International Atherosclerosis Society were formal partners. The Summit was hosted by a Member of the European Parliament, Romana Jerković, and held under the patronage of the Polish presidency of the Council of the European Union. The Declaration calls for 1) integration of Lp(a) testing and management into Global, European and National Cardiovascular Health Plans; 2) appropriate investment, policy and programmes in targeting Lp(a) testing and management based on a recent study demonstrating the substantial overall cost-saving to health systems across the globe; 3) political commitment to mandate systematic Lp(a) testing at least once during a person's lifetime, ideally at an early age, with full reimbursement; 4) incorporation of Lp(a) test results in the context of a person's cardiovascular risk assessment, with development of personalised cardiovascular health roadmaps as needed, without fear of discrimination; 5) investment in public and healthcare professional education to increase awareness of Lp(a) and its impact on cardiovascular health.

Background: The burden of coronary heart disease (CHD) is disproportionately greater among socio-economically disadvantaged groups. Health services play a crucial role in addressing this social gradient by ensuring equitable access to care. However, there is limited evidence on effective strategies to improve health service accessibility for CHD patients, particularly those that are codesigned with people with lived experience and clinicians. The Equal Hearts study aimed to codesign a health literacy-based intervention to improve the accessibility of hospital-based cardiac services for underserved population groups with CHD. Methods: This study employed a mixed-methods approach based on codesign principles. The study comprises three phases: identifying and understanding the problem, codeveloping an intervention, and translating the intervention into practice. Phases 1 and 2 are reported in this paper and included focus groups, interviews and an intervention development workshop. Participants for focus groups and interviews were recruited from four health services in [Victoria] and included patients with CHD, health consumers from culturally diverse communities and clinicians. Findings from focus groups and interviews were analysed via thematic analysis using Levesque's conceptual framework to identify health literacy barriers to accessibility of cardiac services. These barriers were prioritised in a codesign workshop with cardiac patients, health consumers and clinicians. Results: Thirty-seven cardiac patients, 10 clinicians and 44 culturally diverse health consumers participated in focus groups/interviews. Among these participants, eight cardiac patients/carers and five clinicians attended the workshop. Cardiac patients reported a lack of preparedness for hospital discharge and feeling 'lost' and uncertain about how to confidently manage their health at home after a cardiac event. A codesigned intervention-The Patient Discharge Action Plan-aims to improve patients' transition from hospital to home. Conclusions: Using a codesign approach and health literacy principles, a health service intervention was developed to improve accessibility of cardiac services. The Patient Discharge Action Plan is currently being evaluated in a pilot RCT. Two consumer co-authors [L.F.J. and J.H.] informed the development of the study protocol. A Stakeholder Advisory Panel, including six people with lived experience of CHD and four clinicians/health service managers from participating sites, guided all steps within this study. Background: ACTRN12624000780550p (Australian and New Zealand Clinical Trials Registry). Registered on 25 June 2024.

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