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.).

Therapeutic Area ASCVD/CVD Risk Assessment Background To investigate the associations between HDL-C levels with mortality and cardiovascular (CV) events; the safety of increased HDL-C due to CETP inhibition; and the efficacy of CETP as a target of lipid-altering therapy. Methods The cumulative rates of major coronary events, CV mortality, and non-CV mortality were compared among participants in the UK Biobank (n∼445,000) who were randomized by nature to different levels of lifetime exposure to HDL-C (Mendelian randomization [MR]) using an instrumental variable genetic score. The cumulative rates of major coronary events among participants randomized by nature to CETP, HMG CoA reductase, and PCSK9 inhibition was compared for the same absolute reduction in apoB among participants in the UK Biobank or CARDloGRAMplusC4D consortium (n=630,070). A Meta-analysis of RCTs adjusted for magnitude and duration of therapy was used to estimate the association between CETP inhibition induced changes in plasma HDL-C and the risk of both all-cause and CV mortality (n=58,412); and between CETP inhibition and the risk of major CV events, CV mortality, and all-cause mortality (n=42,541). Results There was no compelling unconfounded evidence from observational studies, MR studies, or RCTs that very high plasma HDL-C levels increase risk of all-cause, non-CV, or CV mortality. CETP inhibition is associated with a modestly lower risk of all-cause and CV mortality. There was consistent randomized evidence from MR and RCTs that CETP inhibition reduces risk of major CV events proportional to the achieved reduction in plasma apoB, and by approximately the same amount as statins and PCSK9 inhibitors for the same achieved reduction in apoB. Conclusions Neither naturally occurring elevated HDL-C or therapeutically increased HDL-C due to CETP inhibition are associated with increased all-cause, CV, or non-CV mortality. ApoB reduction induced by CETP inhibition reduces CV risk by approximately the same degree as reductions induced by statins and PCSK9 inhibitors.

Background: Maintaining low levels of low-density lipoproteins (LDL) over time has the potential to substantially reduce the lifetime risk of atherosclerotic cardiovascular disease. However, the optimal timing of lowering LDL to prevent atherosclerotic cardiovascular events is unknown. Methods: We combined evidence from Mendelian randomization studies and randomized trials to develop a causal AI algorithm to estimate the benefit of lowering LDL on the risk of major cardiovascular events (MCVE) in discrete time-units of exposure. We tested the accuracy of this algorithm among 440,371 participants randomized by nature to a partial loss-of-function (LOF) variant in the PCSK9 gene, and 46,488 participants in two large randomized trials of PCSK9 inhibitors. We then used this algorithm to estimate the benefit of lowering LDL using a once-yearly dose of an siRNA directed against PCSK9 beginning at different ages among 2.3 million men and women. Results: The causal AI algorithm accurately estimated the benefit of lifelong lower LDL due to partial loss-of-function of the PCSK9 gene, and the benefit of lowering LDL with a PCSK9 inhibitor starting at a mean age of 61 years, with nearly superimposable observed and predicted event curves. Lowering LDL by 36% was estimated to reduce the lifetime risk of MCVE by 57% (HR: 0.43, 95%CI: 0.39-0.47) if started at age 30, by 48% (HR: 0.52, 95%CI: 0.50-0.54) if started at age 40, by 38% (HR: 0.62, 95%CI: 0.60-0.65) if started at age 50, and by 26% (HR: 0.74, 95%CI: 0.71-0.77) if started at age 60 years. Moderate LDL lowering starting at age 40 years was estimated to have a greater benefit than more aggressively LDL lowering beginning at age 55 years, with a lower residual risk at all ages. In addition, the benefit of earlier LDL lowering persisted throughout life leading to a quantifiable legacy benefit. Conclusions: The benefit of lowering LDL is determined by the magnitude, duration, and timing of LDL lowering. Modest sustained LDL lowering beginning in early to middle adulthood, which can be achieved with a once-yearly dose of a PCSK9 siRNA, may be the optimal strategy to prevent atherosclerotic cardiovascular events by slowing the progression of atherosclerosis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

The availability of pharmacological approaches able to effectively reduce circulating LDL cholesterol (LDL-C) has led to a substantial reduction in the risk of atherosclerosis-related cardiovascular disease (CVD). However, a residual cardiovascular (CV) risk persists in treated individuals with optimal levels of LDL-C. Additional risk factors beyond LDL-C are involved, and among these, elevated levels of triglycerides (TGs) and TG-rich lipoproteins are causally associated with an increased CV risk. Apolipoprotein C-III (apoC-III) is a key regulator of TG metabolism and hence circulating levels through several mechanisms including the inhibition of lipoprotein lipase activity and alterations in the affinity of apoC-III-containing lipoproteins for both the hepatic receptors involved in their removal and extracellular matrix in the arterial wall. Genetic studies have clarified the role of apoC-III in humans, establishing a causal link with CVD and showing that loss-of-function mutations in the APOC3 gene are associated with reduced TG levels and reduced risk of coronary heart disease. Currently available hypolipidaemic drugs can reduce TG levels, although to a limited extent. Substantial reductions in TG levels can be obtained with new drugs that target specifically apoC-III; these include two antisense oligonucleotides, one small interfering RNA and an antibody.

Background Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low -density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] and increases high -density lipoprotein cholesterol (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential to lower atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment with available maximally tolerated lipid -modifying therapies, addressing an unmet medical need in a patient population at high risk for cardiovascular events. Methods and results BROADWAY (NCT05142722) and BROOKLYN (NCT05425745) are ongoing placebocontrolled, double-blind, randomized Phase III trials designed to examine the efficacy, safety, and tolerability of obicetrapib as an adjunct to dietar y inter vention and maximally tolerated lipid -modifying therapies in participants with a history of ASCVD and/or underlying HeFH whose LDL-C is not adequately controlled. The primary efficacy endpoint was the percent change in LDL-C from baseline to day 84. Other endpoints included changes in Apo B, non-HDL-C, HDL-C, Apo A1, Lp(a), and triglycerides in addition to parameters evaluating safety, tolerability, and pharmacokinetics. BROADWAY also included an adjudicated assessment of major adverse cardiovascular events, measurements of glucose homeostasis, and an ambulatory blood pressure monitoring substudy. A total of 2,532 participants were randomized in BROADWAY and 354 in BROOKLYN to receive obicetrapib 10 mg or placebo (2:1) for 365 days with follow-up through 35 days after the last dose. Results from both trials are anticipated in 2024. Conclusion These trials will provide safety and efficacy data to support the potential use of obicetrapib among patients with ASCVD or HeFH with elevated LDL-C for whom existing therapies are not sufficiently effective or well -tolerated. (Am Heart J 2024;274:32-45.)

The trapping of LDL and other apolipoprotein B-containing lipoproteins within the artery wall causes atherosclerosis. As more LDL becomes trapped within the artery wall over time, the atherosclerotic plaque burden gradually increases, raising the risk of an acute cardiovascular event. Therefore, the biological effect of LDL on the risk of atherosclerotic cardiovascular disease (ASCVD) depends on both the magnitude and duration of exposure. Maintaining low levels of LDL-cholesterol (LDL-C) over time decreases the number of LDL particles trapped within the artery wall, slows the progression of atherosclerosis and, by delaying the age at which mature atherosclerotic plaques develop, substantially reduces the lifetime risk of ASCVD events. Summing LDL-C measurements over time to calculate cumulative exposure to LDL generates a unique biomarker that captures both the magnitude and duration of exposure, which facilitates the estimation of the absolute risk of having an acute cardiovascular event at any point in time. Titrating LDL-C lowering to keep cumulative exposure to LDL below the threshold at which acute cardiovascular events occur can effectively prevent ASCVD. In this Review, we provide the first comprehensive overview of how the LDL cumulative exposure hypothesis can guide the prevention of ASCVD. We also discuss the benefits of maintaining lower LDL-C levels over time and how this knowledge can be used to inform clinical practice guidelines as well as to design novel primary prevention trials and ASCVD prevention programmes. In this Review, Catapano and colleagues discuss the evidence supporting the LDL cumulative exposure hypothesis and how measuring cumulative LDL exposure can be used to estimate risk and contribute to the prevention of atherosclerotic cardiovascular disease.

Background/Synopsis Obicetrapib, an orally delivered cholesteryl ester transfer protein inhibitor, reduces concentrations of atherogenic lipid parameters and increases HDL-C when added to statins. Objective/Purpose BROOKLYN examined the efficacy, safety, and tolerability of obicetrapib 10 mg, as an adjunct to maximally tolerated lipid-modifying therapies, in patients with heterozygous familial hypercholesterolemia (HeFH) and suboptimal LDL-C control. Methods This was a phase 3, randomized, double-blind, placebo-controlled trial NCT05425745 with 1 year follow up in 354 patients across 70 sites. Participants (n = 354) with HeFH and fasting LDL-C ³70 mg/dL taking maximally tolerated lipid-modifying therapies were randomly assigned to receive obicetrapib 10 mg or matching placebo orally daily for 52 weeks in a 2:1 ratio. Study primary endpoint assessed obicetrapib compared with placebo in LS mean percent change from baseline to week 12 in LDL-C. Secondary endpoints included obicetrapib compared with placebo in percent changes from baseline in Apo B, non-HDL-C, HDL-C, total-C, Lp(a), and TG, and safety measures; Apo A1 was an exploratory endpoint. Results Mean baseline lipoprotein lipid levels for obicetrapib and placebo, respectively, were LDL-C: 123.4 and 119.9 mg/dL; ApoB: 107.2 and 105.3 mg/dL; non-HDL-C: 148.4 and 146.7 mg/dL; and HDL-C: 53.2 and 50.2 mg/dL. Obicetrapib, compared with placebo, significantly reduced mean LDL-C -36.3% at day 84 (P < 0.0001) and -41.5% at day 365 (P < 0.0001). On day 84 and day 365, obicetrapib, compared with placebo, significantly reduced mean ApoB -24.4%, -25.8%; non-HDL-C -34.5%, -37.5%; Lp(a) -45.9%, -54.3%; and increased HDL-C 138.7%, 121.4%, respectively. Obicetrapib was well tolerated with no serious adverse events or clinically significant changes in vital signs, electrocardiograms, or other clinical laboratory values. Conclusions Obicetrapib, as an adjunct to maximally tolerated lipid-modifying therapies, produced significant LDL-C lowering at day 84 with sustained effect through day 365 in patients with HeFH. Obicetrapib holds promise for patients with HeFH who are unable to attain their LDL-C treatment targets with available lipid-lowering agents.Previously Published: American Heart Association (AHA) Scientific Sessions 2024:Circulation. 2024; 150: e712- e729 - e73

Background and Aims: We sought to compare the association between the proportional risk reduction in major cardiovascular events (MCE) and different classes of lipid-lowering therapies (LLT) for the same magnitude and duration of apolipoprotein-B (apoB) lowering. Methods: MEDLINE and EMBASE databases were searched (1966-November 2022). Key inclusion criteria were: randomized controlled trials; adjudicated clinical cardiovascular outcomes; enrolled at least 1000 participants; with median follow-up at least one year; and reported absolute achieved difference in plasma apoB levels between the treatment and control groups. Data were analysed using inverse variance-weighted meta-analysis after each year of follow-up. Results: A total of 254,828 participants (mean age 63 years; 26% female sex) from 20 trials who experienced 30,175 MCE were included. For each 30 mg/dL absolute reduction in plasma apoB levels, statins, ezetimibe, PCSK9-inhibitors, CETP-inhibitors, fibrates, and niacin were each associated with a consistent 10% proportional reduction in MCE after one year of therapy (HR:0.90; 95%CI:0.86-0.94); 15% reduction after two years of therapy (HR:0.85; 95%CI:0.82-0.88); 19% reduction after three years of therapy (HR:0.81; 95%CI:0.78-0.85); and a 20% reduction after four or five years of therapy (HR:0.80; 95%CI:0.77-0.83). There was no evidence of heterogeneity between estimates of the different LLT classes (I2=6.9%; p-value=0.364). Conclusions: In this meta-analysis, six different classes of LLT were associated with very similar reductions in the risk of MCE for the same magnitude and duration of apoB lowering, suggesting that the clinical benefit of LLT is determined by the achieved changes in plasma apoB levels, regardless of the corresponding changes in other lipids.

Background and Aims: We aimed at assessing the impact of family history of coronary heart disease (CHD) and genetic predisposition in predicting the individual lifetime risk of major coronary events (MCE). Methods: Using adjusted Cox proportional hazard models, we estimated the lifetime risk of MCE associated with parental family history of CHD and individual genetic predisposition (estimated through a polygenic score). Results: A total of 445,744 UK-Biobank participants were selected (mean age 57 years; 54.3% females). Having one parent with a history of CHD increased the lifetime risk of MCE by 75% (HR 1.75, 95%CI 1.70-1.82, p-value<0.0001). Having both parents with a history of CHD further increased the risk (HR 2.78, 95%CI 2.64-2.92, p-value<0.0001) Similarly, a dose-dependent step-wise increase in MCE risk was observed moving from the lowest to the highest decile of the polygenic score. Compared to subjects without family history of CHD and with average level of the polygenic score, having a parental history of CHD determined an increase in lifetime risk of MCE (HR 1.90, 95%CI 1.82-1.98, p-value<0.0001) comparable to belonging to the highest decile of the polygenic score (HR 1.89, 95%CI 1.76-2.02, p-value<0.0001). However, if subjects present both parents with family history of CHD and a very high polygenic predisposition, the risk was even higher (HR 3.54, 95%CI 3.34-3.75, p-value<0.0001), suggesting an additive contribution. Conclusions: We described the additive impact of family history of CHD and individual polygenic predisposition in predicting lifetime risk of MCE. Therefore, it is essential to retrieve information about both these hereditary components to identify subjects at higher risk.

In 2022, the European Atherosclerosis Society (EAS) published a new consensus statement on lipoprotein(a) [Lp(a)], summarizing current knowledge about its causal association with atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. One of the novelties of this statement is a new risk calculator showing how Lp(a) influences lifetime risk for ASCVD and that global risk may be underestimated substantially in individuals with high or very high Lp(a) concentration. The statement also provides practical advice on how knowledge about Lp(a) concentration can be used to modulate risk factor management, given that specific and highly effective mRNA-targeted Lp(a)-lowering therapies are still in clinical development. This advice counters the attitude: "Why should I measure Lp(a) if I can't lower it?". Subsequent to publication, questions have arisen relating to how the recommendations of this statement impact everyday clinical practice and ASCVD management. This review addresses 30 of the most frequently asked questions about Lp(a) epidemiology, its contribution to cardiovascular risk, Lp(a) measurement, risk factor management and existing therapeutic options.

IMPORTANCE:Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content. OBJECTIVE:To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins. DESIGN, SETTING, AND PARTICIPANTS:This prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389 529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40 430 patients with established atherosclerosis who were receiving statin treatment. EXPOSURES:ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG. MAIN OUTCOME AND MEASURES:The primary study outcome was incident myocardial infarction (MI). RESULTS:Of the 389 529 individuals in the primary prevention group, 224 097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40 430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P < .001). Similarly, only apoB was associated with MI in the secondary prevention cohort. Adjusting for apoB, there was no association between the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL) and risk of MI, implying that for a given concentration of apoB-containing lipoproteins, the relative proportions of particle subpopulations may no longer be a predictor of risk. CONCLUSIONS AND RELEVANCE:In this cohort study, risk of MI was best captured by the number of apoB-containing lipoproteins, independent from lipid content (cholesterol or TG) or type of lipoprotein (LDL or TG-rich). This suggests that apoB may be the primary driver of atherosclerosis and that lowering the concentration of all apoB-containing lipoproteins should be the focus of therapeutic strategies.

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Background and Aims : Lp(a) concentration has been associated to increased risk of atherosclerotic cardiovascular disease (ASCVD). Whether ASCVD risk varies between LPA genotype or measured Lp(a) levels is still unknown.Methods: A total of 445,744 participants enrolled in the UK-Biobank with complete genetic and principal component data were included in the study. For each participant, we calculated the LPA genetic risk score by summing the number of risk-increasing alleles inherited at rs3798220 and rs10455872 variants, weighted by the effect size of each allele. The primary outcome was major coronary event (MCE), a composite of fatal or non-fatal myocardial infarction, or coronary revascularization. Using adjusted Cox proportional hazards models and Kaplan-Meier curves, we compared the cumulative lifetime risk of MCE among subjects with different LPA genotype and measured Lp(a) concentrations.Results: Participants with one copy of either rs10455872 or rs3798220 had a hazard ratio (HR) for MCE of 1.47 (95%CI: 1.42-1.51) compared with wild-type subjects (median Lp(a): 146.3 nmol/L and 13.6 nmol/L, respectively). Stratifying the population according to measured Lp(a) concentrations comparable to those observed for the genetic risk score, we found similar rate of incident MCE for the same Lp(a) change (HR 1.47, 95%CI: 1.41-1.53). Even among subjects with the same LPA genotype, increasing quintiles of Lp(a) concentration were associated with a step-wise increase in MCE risk.Conclusions: Our results demonstrated that LPA genetic risk score and measured Lp(a) concentrations provide comparable risk prediction for incident MCE. In terms of cardiovascular risk prediction, it is reasonable to rely on clinically measured Lp(a) levels, regardless of genotype. Background and Aims : Lp(a) concentration has been associated to increased risk of atherosclerotic cardiovascular disease (ASCVD). Whether ASCVD risk varies between LPA genotype or measured Lp(a) levels is still unknown. Methods: A total of 445,744 participants enrolled in the UK-Biobank with complete genetic and principal component data were included in the study. For each participant, we calculated the LPA genetic risk score by summing the number of risk-increasing alleles inherited at rs3798220 and rs10455872 variants, weighted by the effect size of each allele. The primary outcome was major coronary event (MCE), a composite of fatal or non-fatal myocardial infarction, or coronary revascularization. Using adjusted Cox proportional hazards models and Kaplan-Meier curves, we compared the cumulative lifetime risk of MCE among subjects with different LPA genotype and measured Lp(a) concentrations. Results: Participants with one copy of either rs10455872 or rs3798220 had a hazard ratio (HR) for MCE of 1.47 (95%CI: 1.42-1.51) compared with wild-type subjects (median Lp(a): 146.3 nmol/L and 13.6 nmol/L, respectively). Stratifying the population according to measured Lp(a) concentrations comparable to those observed for the genetic risk score, we found similar rate of incident MCE for the same Lp(a) change (HR 1.47, 95%CI: 1.41-1.53). Even among subjects with the same LPA genotype, increasing quintiles of Lp(a) concentration were associated with a step-wise increase in MCE risk. Conclusions: Our results demonstrated that LPA genetic risk score and measured Lp(a) concentrations provide comparable risk prediction for incident MCE. In terms of cardiovascular risk prediction, it is reasonable to rely on clinically measured Lp(a) levels, regardless of genotype.

Health economic analyses are essential for health services research, providing decision-makers and payers with evidence about the value of interventions relative to their opportunity cost. However, many health economic approaches are still limited, especially regarding the primary prevention of cardiovascular disease (CVD). In this article, we discuss some limitations to current health economic models and then outline an approach to address these via the incorporation of genomics into the design of health economic models for CVD. We propose that when a randomised clinical trial is not possible or practical, health economic models for primary prevention of CVD can be based on Mendelian randomisation analyses, a technique to assess causality in observational data. We discuss the advantages of this approach, such as integrating well-known disease biology into health economic models and how this may overcome current statistical approaches to assessing the benefits of interventions. We argue that this approach may provide the economic argument for integrating genomics into clinical practice and the efficient targeting of newer therapeutics, transforming our approach to the primary prevention of CVD, thereby moving from reactive to preventive healthcare. We end by discussing some limitations and potential pitfalls of this approach.

Background and Aims : Lipoprotein(a) is an apoB-containing lipoprotein attached to an apolipoprotein(a) and is causally associated with the risk of cardiovascular disease. Because the apo(a) moiety has sequence homology with plasminogen, Lp(a) may be prothrombotic. We therefore sought to determine whether Lp(a) has a clinically significant venous or arterial prothrombotic effect.Methods: We used Mendelian randomization to evaluate the causal effect of Lp(a) on the risk of venous thromboembolism (VTE) among participants in the UK-Biobank. We then evaluated the causal effect of Lp(a) on the risk of myocardial infarction (MI) in the entire study sample, and stratified by genetic scores that mimic the effect of antiplatelet and antithrombin therapies.Conclusions: Lp(a) does not have a clinically significant venous or arterial prothrombotic effect. Therefore, the increased risk of MI caused by elevated Lp(a) is unlikely to be reduced by treatment with either an antiplatelet or antithrombin therapy. Background and Aims : Lipoprotein(a) is an apoB-containing lipoprotein attached to an apolipoprotein(a) and is causally associated with the risk of cardiovascular disease. Because the apo(a) moiety has sequence homology with plasminogen, Lp(a) may be prothrombotic. We therefore sought to determine whether Lp(a) has a clinically significant venous or arterial prothrombotic effect. Methods: We used Mendelian randomization to evaluate the causal effect of Lp(a) on the risk of venous thromboembolism (VTE) among participants in the UK-Biobank. We then evaluated the causal effect of Lp(a) on the risk of myocardial infarction (MI) in the entire study sample, and stratified by genetic scores that mimic the effect of antiplatelet and antithrombin therapies. Conclusions: Lp(a) does not have a clinically significant venous or arterial prothrombotic effect. Therefore, the increased risk of MI caused by elevated Lp(a) is unlikely to be reduced by treatment with either an antiplatelet or antithrombin therapy.

BACKGROUND AND AIMS:Post hoc analyses of clinical trials show that PCSK9 inhibitors might lower lipoprotein(a), but whether this effect contributes to reductions in cardiovascular risk remains unknown. We aimed to assess whether genetically proxied PCSK9 inhibition influences lipoprotein(a) (Lp(a)), and whether any such effect could mediate its effects on coronary artery disease (CAD) and ischemic stroke (IS). METHODS:To explore associations between the genetic proxies for PCSK9 inhibitors and Lp(a) levels, we used UK Biobank data (310,020 individuals). We identified 10 variants in the PCSK9 gene associated with lower PCSK9 and LDL-C levels as proxies for PCSK9 inhibition. We explored the effects of genetically proxied PCSK9 inhibition on Lp(a) levels, as well as on odds of CAD (60,801 cases, 184,305 controls) and IS (60,341 cases, 454,450 controls) in two-sample Mendelian randomization analyses. In mediation analyses, we assessed the effects of genetically proxied PCSK9 inhibition on CAD and IS mediated through reductions in Lp(a) levels. RESULTS:Genetically proxied PCSK9 inhibition (1-SD decrement in PCSK9 concentration; corresponding to 20.6 mg/dl decrement in LDL-C levels) was associated with a 4% decrease in log-Lp(a) levels (beta: -0.038, 95%CI: -0.053 to -0.023). We estimated a 0.8% reduction in the odds for CAD (OR: 0.992, 95%CI: 0.989-0.995) and a 0.5% reduction in the odds for atherosclerotic IS (OR: 0.995, 95%CI: 0.992-0.998) due to reductions in Lp(a) levels through genetically proxied PCSK9 inhibition, corresponding to 3.8% and 3.2% of the total effects, respectively. CONCLUSIONS:Genetic proxies for PCSK9 inhibition are associated with lower Lp(a) levels. However, Lp(a) lowering explains only a small proportion of the total effects of genetic proxies for PCSK9 inhibitors on risk of CAD and IS.

Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content.To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins.This prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389 529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40 430 patients with established atherosclerosis who were receiving statin treatment.ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG.The primary study outcome was incident myocardial infarction (MI).Of the 389 529 individuals in the primary prevention group, 224 097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40 430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P < .001). Similarly, only apoB was associated with MI in the secondary prevention cohort. Adjusting for apoB, there was no association between the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL) and risk of MI, implying that for a given concentration of apoB-containing lipoproteins, the relative proportions of particle subpopulations may no longer be a predictor of risk.In this cohort study, risk of MI was best captured by the number of apoB-containing lipoproteins, independent from lipid content (cholesterol or TG) or type of lipoprotein (LDL or TG-rich). This suggests that apoB may be the primary driver of atherosclerosis and that lowering the concentration of all apoB-containing lipoproteins should be the focus of therapeutic strategies.

AIMS:Reliably quantifying event rates in secondary prevention could aid clinical decision-making, including quantifying potential risk reductions of novel, and sometimes expensive, add-on therapies. We aimed to assess whether the SMART risk prediction model performs well in a real-world setting.METHODS AND RESULTS:We conducted a historical open cohort study using UK primary care data from the Clinical Practice Research Datalink (2000-2017) diagnosed with coronary, cerebrovascular, peripheral, and/or aortic atherosclerotic cardiovascular disease (ASCVD). Analyses were undertaken separately for cohorts with established (≥6 months) vs. newly diagnosed ASCVD. The outcome was first post-cohort entry occurrence of myocardial infarction, stroke, or cardiovascular death. Among the cohort with established ASCVD [n = 244 578, 62.1% male, median age 67.3 years, interquartile range (IQR) 59.2-74.0], the calibration and discrimination achieved by the SMART model was not dissimilar to performance at internal validation [Harrell's c-statistic = 0.639, 95% confidence interval (CI) 0.636-0.642, compared with 0.675, 0.642-0.708]. Decision curve analysis indicated that the model outperformed treat all and treat none strategies in the clinically relevant 20-60% predicted risk range. Consistent findings were observed in sensitivity analyses, including complete case analysis (n = 182 482; c = 0.624, 95% CI 0.620-0.627). Among the cohort with newly diagnosed ASCVD (n = 136 445; 61.0% male; median age 66.0 years, IQR 57.7-73.2), model performance was weaker with more exaggerated risk under-prediction and a c-statistic of 0.559, 95% CI 0.556-0.562.CONCLUSIONS:The performance of the SMART model in this validation cohort demonstrates its potential utility in routine healthcare settings in guiding both population and individual-level decision-making for secondary prevention patients.