Welcome to the EAS 2022 Interactive Program

Background and Aims

VLDL and remnant cholesterol are increasingly recognized risk factors for MI with few targeted therapeutic options. Vupanorsen is an antisense oligonucleotide that inhibits the synthesis of ANGPTL3, a regulator of cholesterol metabolism.

Methods

TRANSLATE-TIMI 70 was a double-blind, randomized controlled trial testing 7 dose regimens of vupanorsen (SC Q4W: 80, 120, 160 mg; SC Q2W: 60, 80, 120, 160 mg) in adults with elevated triglycerides (150-500 mg/dl) and non-HDL-C ≥100 mg/dl on statin therapy. ANGPTL3, direct VLDL-C, and remnant cholesterol (calculated as total cholesterol - direct LDL-C - HDL-C) were assessed over 24 weeks.

Results

286 patients were enrolled with a median age of 64 years (IQR 58-69) and 44% female. Mean baseline VLDL and remnant cholesterol levels were 35 and 45 mg/dl, respectively (both normally <30 mg/dl). Vupanorsen lowered VLDL-C by up to 66-88% over placebo (p<0.001) at 16-24 weeks in the 160 mg Q2W arm (Figure, A), achieving a mean level of 7-8 mg/dl. Over the same time frame, remnant cholesterol was also significantly reduced by up to 57-59% over placebo (p<0.001). The magnitude of VLDL and remnant cholesterol reduction was directly related to the degree of ANGPTL3 protein synthesis inhibition (Figure, B), which occurred in a dose-dependent manner and by as much as 95% compared with placebo (p<0.001).

Conclusions

Inhibition of ANGPTL3 protein synthesis significantly lowers VLDL and remnant cholesterol, with the magnitude of reduction directly related to degree of ANGPTL3 lowering. ANGPTL3 inhibition may have a role in patients with residual dyslipidemia despite LDL-lowering therapy.

Background and Aims

Background: As guidelines now recommend lower LDL-C goals, means that many patients require additional lipid lowering therapies (LLT) to attain risk based LDL-C goals despite use of high intensity statins (HIS). Cost and/or efficacy of current LLT options have limited their uptake in clinical practice. Mendelian randomization and RCT trial data support CETP inhibition as a validated target to reduce LDL-C and cardiovascular risk. Safety and efficacy concerns have to date limited the development of CETPi. Previously the selective CETPi obicetrapib demonstrated LDL-C lowering up to 45% as monotherapy.

Aims: To assess the effects of obicetrapib on LDL-C and lipid parameters in patients on HIS.

Methods

Methods: 120 patients with LDL-C ≥70 mg/dL, despite HIS, were randomized to obicetrapib 5 or 10 mg or placebo for 8 weeks. The primary endpoint was percent change in LDL-C, secondary endpoints included changes in other lipids, exploratory analyses evaluated goal attainment.

Results

Results: Obicetrapib produced dose-dependent lowering of LDL-C, ApoB and non-HDL-C (up to 50.8%, 29.8% and 44.4% respectively, P<0.0001 for each, Table). Approximately 2/3 of patients achieved LDL-C < 55mg/dl when Obicetrapib was added to HIS vs PL. Fewer patients in the OBI arms experienced treatment emergent adverse events vs placebo (26 vs 48%) with no clinically significant changes in laboratory parameters, vital signs, or physical examinations.

Conclusions

Conclusion: Obicetrapib 5 and 10 mg produced robust decreases in LDL-C, ApoB and Non-HDL-C with greater attainment of lipid goals in the majority of patients treated with HIS and was well tolerated.

Background and Aims

Angiopoietin-like protein 3 (ANGPTL3) inhibition reduces LDL-cholesterol (LDL-C), triglycerides (TG) and HDL-C in patients with hyperlipidemia. Post-prandially, ANGPTL8 forms a complex with ANGPTL3; the ANGPTL3/8 complex inhibits lipoprotein lipase 100-fold more potently and circulates at much lower levels than ANGPTL3 alone. This phase 1 study assessed the safety and pharmacology of single ascending doses of LY3475766 (LY), a monoclonal antibody against the ANGPTL3/8 complex.

Methods

This 28-day, randomized, double-blind, placebo-controlled study enrolled 48 subjects (36 males/12 females) with TG >135 mg/dL and LDL-C ≥70 mg/dL who were assigned (6:2) to receive 1 dose of LY or placebo intravenously (10 - 30mg) or subcutaneously (100 - 600mg). LY pharmacokinetics, fasting lipids, apolipoproteins, vital signs, laboratory data, and adverse events (AEs) were measured.

Results

LY reached maximum concentration 27-108 hours after subcutaneous injection; half-life for 600mg LY was 106 hours. Two weeks after LY subcutaneous injection, TG, remnant-cholesterol, LDL-C, non-HDL-C, and apolipoprotein B decreased dose-dependently. HDL-C increased with the two highest doses. Most common AEs were mild or moderate injection-site reactions, with no serious AEs or discontinuations due to AEs during the study.

Median percent change from baseline in fasting triglycerides (a) and remnant-cholesterol (b) and mean percent change from baseline in fasting LDL-C (c) and non-HDL-C (d) up to 28 days after single doses of LY3475766 or placebo. Intravenous doses (10mg and 30mg) not shown. (Remnant cholesterol=[total cholesterol]–[LDL-C]–[HDL-C]; LDL-C=LDL-cholesterol; HDL-C=HDL-cholesterol; LDL-C=LDL-cholesterol; SC=subcutaneous).

Conclusions

Inhibition of ANGPTL3/8 complex with LY reduced TG, remnant-cholesterol, LDL-C, non-HDL-C, and apolipoprotein B and increased HDL-C in patients with hyperlipidemia.

Background and Aims

HDL-mediated cholesterol efflux capacity (CEC) measures the ability of HDL particles to induce efflux of cholesterol from macrophages. This functionality of HDL particles may protect from atherosclerosis. Indeed, several studies have shown an inverse association of CEC with prevalent and incident cardiovascular disease. However, to test for causality we need to know more about the genetic architecture of CEC.

Methods

We measured CEC in the German Chronic Kidney Disease (GCKD) study (n=5,171) using J774A.1 macrophages. Cells were labelled with BODIPY-cholesterol, stimulated with cAMP and efflux was performed for four hours to 2% apolipoprotein B-depleted serum. Multivariable regression analysis was performed to determine variables independently associated with CEC. Genome-wide association analysis (GWAS) was performed using REGENIE with the nf-gwas Nextflow pipeline (https://github.com/genepi/nf-gwas).

Results

HDL-cholesterol and triglyceride concentrations were the most important variables associated with CEC, explaining 11.8% and 12.9% of the variance in CEC values, respectively. In our main GWAS model adjusted for age, sex and principal components 1-10, the KLKB1 locus (chromosome 4) and APOE/C1 locus (chromosome 19) were significantly associated with CEC (p=8.8x10^-10 and p=3.3x10^-10, respectively). The association of the KLKB1 locus was independent of estimated glomerular filtration rate, albuminuria, HDL-cholesterol and triglycerides while the association with the APOE/C1 locus was mediated by triglycerides. Additional adjustment for triglycerides also revealed the CLSTN2 locus (chromosome 3) that was borderline significant in our main model (p=2.0x10^-7).

Conclusions

We confirmed the previously reported association of the APOE/C1 locus and report two novel loci (KLKB1 and CLSTN2) that are associated with CEC.

Background and Aims

Familial Hypercholesterolaemia (FH) affects 25-35 million globally of whom 20-25% are children/adolescents. The FH Studies Collaboration (FHSC) showed that <2.5% of heterozygous FH (HeFH) adult cases were diagnosed age <18 years. Informing contemporary approaches to large-scale case finding before adulthood could be aided through evaluation of the paediatric cohort within the FHSC registry. We aimed to characterise children/adolescents with HeFH and describe how they were detected and managed globally.

Methods

The FHSC comprises regional/national data from multiple cohorts/registries/databases of children and adults with a clinical and/or genetic diagnosis of FH. We conducted cross-sectional analyses at registry entry of <18-year-old patients with HeFH from 44 countries.

Results

We included 11,231 children (50% girls, age at diagnosis: median 9.1 years, IQR: 5.3-13.0; 96.2% from high-income countries); 85.7% underwent genetic testing, 67.0% were non-index cases, 3.2% were identified through formal universal screening. Corneal arcus and xanthoma were present in 0.9% and 2.2% respectively, 0.3% had CAD. LDL-C levels are shown in the figure with no differences by sex; 27.9% were on lipid-lowering medications at registry entry (age ≤9: 23.0%; >9: 32.1%); overall 13.4% had an LDL-C <130mg/dL.

Conclusions

FH detection outside high-income countries is low. Classic clinical signs are scarce suggesting diagnosis is reliant on LDL-C levels or genetic testing (if available/accessible). Identification largely occurred opportunistically or through cascade screening and these methods are likely to underserve the current and future generations of children with FH as only a fraction will be identified. These findings have implications for future public health strategies.

Background and Aims

Understanding presymptomatic perturbations in circulating lipid species across a range of disorders could provide therapeutic targets and mechanistic insights into their shared and heterogenous pathophysiology. Here we aimed to determine alterations in plasma lipidomes (179 lipid species) of healthy individuals (GeneRISK, N=7,169) associated with increased susceptibility for 51 common disorders and traits using polygenic risk scores (PRS).

Methods

Lipidomes were measured by mass spectrometry-based analysis. Genome-wide PRS for type 2 diabetes (T2D), cardiovascular diseases (CVD), liver and kidney function markers, sex hormones, cancers, psychiatric and neurological disorders were estimated using PRS-CS.

Results

For traits with both PRS and direct measurements (e.g., BMI, LDL-C), strong correlation between effects of PRS and direct measurements on lipidome suggested that PRSs capture underlying lipid dysfunctions (Figure 1). Overall, 802 PRS-lipid associations (P_(corrected)<7.0x10^-4) involving 36 PRSs and 156 lipids were identified. PRSs for T2D and sex-hormone binding globulin were associated with most lipids (>85), with strong correlation between their effects (R²=0.82) despite low correlations between corresponding PRSs, suggesting shared mechanism. However, PRSs for glucose and HbA1c showed association with only a few lipids, adding to the existing evidence of heterogeneity in T2D pathophysiology. Sphingolipids with suggested biological role in CVDs were associated with PRS for venous thromboembolism but not with PRSs for coronary artery disease or other CVD traits, pointing to heterogeneity in CVDs.

Conclusions

Our results provide insights into lipid dysfunctions in genetic predisposition for a range of complex traits, and demonstrate potential of the approach in gaining mechanistic insights into disease mechanisms.

Background and Aims

Statin treatment did not reduce the risk of cardiovascular events in hemodialysis patients in the 4D and AURORA trials. Cholesterol absorption was associated with vascular risk and risk reduction by atorvastatin in the 4D study.

Methods

AURORA is a randomized, double-blind, placebo-controlled, multicenter trial in hemodialysis patients. The participants were randomly assigned to receive either rosuvastatin, 10 mg daily, or matching placebo. There was a follow-up for cardiovascular death with a median duration of 3.9 years. The cholestanol to cholesterol ratio was used to estimate cholesterol absorption.

Results

Measurement of non-cholesterol sterols was available in 2,332 participants of the 2,733 patients included in the primary analysis of the AURORA study. A total of 598 participants died from cardiovascular diseases. The 3^rd vs. the 1^st tertile of the cholestanol to cholesterol ratio was significantly associated with increased risk of cardiovascular death (Hazard ratio [95% confidence interval] = 1.36 [1.11-1.65]) in univariate (p = 0.002) and multivariate models (p = 0.034). There was no significant interaction between the cholestanol to cholesterol tertiles and treatment group in predicting cardiovascular death.

Conclusions

The present data from the AURORA Study confirm that high cholesterol absorption is associated with increased cardiovascular risk in hemodialysis patients. Assessment of the individual cholesterol absorption rate to guide initiation of statin treatment is not supported by the findings in the AURORA Study.

Background and Aims

Background: High total leukocyte and neutrophil counts and the ratio between them have been associated with high risk of cardiovascular disease. Specific ischemic vascular endpoints have however not been investigated and the causal potential of such associations remains unexplored. Our aim was to examine the associations between blood leukocyte subpopulation counts and risk of specific ischemic vascular endpoints using observational and genetic studies.

Methods

Methods: Observationally, we included 101,730 participants from the prospective Copenhagen General Population Study. Ischemic vascular endpoints were coronary artery disease (CAD), myocardial infarction (MI), ischemic cerebrovascular disease (ICVD), ischemic stroke (IS), non-Alzheimer’s dementia (non-AD), and vascular dementia (VD). Genetically, we applied a two-sample Mendelian Randomization (MR) design including 438,847 individuals.

Results

Results: Multivariable adjusted hazard ratios (HR) (95% confidence interval) for individuals in the 95-100^th versus the 25-75^th percentile group of neutrophil counts were 1.22 (1.10-1.36) for CAD, 1.22 (1.02-1.45) for MI, and 1.29 (1.05-1.59) for non-AD. Odds ratios (95% confidence interval) per one-SD increase in genetically determined neutrophil counts were 1.14 (1.05-1.23) for CAD and 1.22 (1.06-1.41) for MI. A series of sensitivity analyses accounting for pleiotropy, invalid genetic instruments, and outliers were applied and showed similar results. No genetic estimates could be generated for ICVD, non-AD and VD, due to lack of available genomic consortia.

Conclusions

Conclusion: High blood neutrophil counts were observationally and genetically associated with risk of CAD and MI. The present novel findings support a direct role for neutrophils in atherosclerosis development and highlight these pathways as potential drug targets.