Welcome to the EAS 2023 Interactive Program

Background and Aims

Available PCSK9 inhibitors have demonstrated significant reductions in LDL-C but their injectable route of administration and access barriers have resulted in limited utilization. This study evaluated the efficacy and safety of MK-0616, an oral PCSK9 macrocyclic peptide inhibitor, in participants with hypercholesterolemia.

Methods

This Phase 2b, double-blind, placebo-controlled, multicenter study randomized 381 (380 treated) adult participants with a wide range of ASCVD risk to MK-0616 (6, 12, 18, or 30 mg QD) or matching placebo (1:1:1:1:1 ratio). The primary endpoints included percent change from baseline in LDL-C at Week 8 and the proportion of participants with adverse events (AE) and study intervention discontinuations due to AEs over the 8-week treatment period and additional 8-week follow-up period. Secondary efficacy endpoints included percent change in ApoB and non-HDL-C.

Results

Median age was 62 years and 49% of participants were female. All MK-0616 doses demonstrated statistically significant (p<0.001) differences in LS mean percent change in LDL-C from baseline to Week 8 vs. placebo (Figure). Secondary efficacy endpoints were consistent with the primary endpoint. The proportion of participants with AEs was similar between the MK-0616 arms (39.5% to 43.4%) and placebo (44.0%); ≤2 participants in any treatment arm discontinued intervention due to AEs.

Conclusions

MK-0616 demonstrated statistically significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at Week 8 from baseline and was well tolerated over 8 weeks of treatment and an additional 8 weeks of follow-up. (Ballantyne et al. J Am Coll Cardiol. 2023: S0735-1097(23)00412-6.)

Figure: LDL-C Reduction with MK-0616 vs. Placebo after 8 weeks of Treatment

Background and Aims

SANTORINI is the first study since the 2019 ESC/EAS lipid guidelines which investigates how lipid management evolved in clinical practice after lower LDL-C goal recommendations.

Methods

A multicentre, observational, European study (NCT04271280) conducted between March 2020 and February 2021 with a follow-up until 31 May 2022, assessing approaches of lipid management in patients with high and very high-cardiovascular (CV) risk over 1-year.

Results

Of 9136 patients enrolled, 7210 had LDL-C values available at baseline and at 1-year follow-up. Physicians classified patients into high (28.2%) and very high CV-risk (71.8%) groups. Overall, mean LDL-C in both risk groups was lower at follow-up vs baseline, irrespective of CV risk status (overall: 1.98 vs 2.42 mmol/L; high risk: 2.29 vs 2.74 mmol/L; very high risk: 1.86 vs 2.29 mmol/L). More patients reached LDL-C goals at follow-up vs baseline (high risk: 34.2% vs 24.4%, very high risk: 30.1% vs 20.0%; Table 1A). Overall, high-intensity statin use increased at follow-up in both monotherapy and in combination with ezetimibe. Combination therapy use increased at follow-up in both categories (high risk: 30.8% vs 21.6%; very high risk: 45.3% vs 29.8%; Table 1B). Compared to baseline, an increase in the use of combination therapies was observed in patients achieving LDL-C goal at 1-year follow-up in both categories (Figure 1).

Conclusions

The SANTORINI study suggests that with an increased use of combination therapies, a higher proportion of high and very high-CV risk patients reach their LDL-C goals. Using combination therapies as standard of care should improve the proportion of patients at goal.

Background and Aims

Inclisiran, an siRNA therapy, provides sustained reductions in LDL-C. Potential CV benefits of inclisiran, as an adjunct to statins, were evaluated through simulation.

Methods

Ten-year CV risk (RISK10) was estimated using the SMART equation in patients with ASCVD from the ORION-10 and ORION-11 trials, comparing inclisiran vs placebo. Change in RISK10 (mean [SD]) between groups was estimated with Cholesterol Treatment Trialists risk ratio for major vascular events using change from baseline in time-averaged LDL-C between Days 90–540. Impact on population health in 500,000 hypothetical ORION‑like inclisiran-treated patients was estimated by Monte Carlo simulation.

Results

Baseline characteristics in inclisiran (n=1288) and placebo (n=1264) arms were similar (LDL-C 2.7 mmol/L [0.9] vs 2.6 mmol/L [0.9] and RISK10 24.9% [14.2] vs 24.6% [14.5], respectively). Change in time-adjusted LDL-C was −1.3 mmol/L (0.7) with inclisiran vs −0.004 mmol/L (0.6) with placebo (p<0.001). The predicted RISK10 was 18.1% (10.8) with inclisiran vs 24.7% (15.1) with placebo, corresponding to absolute and relative risk reductions with inclisiran of 7.0% (95% CI 6.7–7.3) and 27.5% (95% CI 26.6–28.3), respectively. Additionally, Monte-Carlo simulation based on baseline RISK10, and LDL-C predicted this approach might avert CV events in 31,522 individuals (6.3% of the hypothetical population) over 10 years, assuming no other lipid-lowering therapies were added.

Conclusions

Simulation using known measures of risk and benefit suggest that sustained reductions in LDL-C achieved with inclisiran could provide substantial population health benefits. The effect of inclisiran on CV outcomes is being evaluated in the ORION-4 and VictORION-2 Prevent trials.

Background and Aims

Adiponectin, an adipocyte-secreted protein-hormone, may play an important protective role in heart failure and associated cardiovascular diseases through insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties. We hypothesized that plasma adiponectin is associated observationally and causal, genetically with risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction.

Methods

In the Copenhagen General Population Study (CGPS), we examined 30,045 individuals with plasma adiponectin measurements observationally and 96,903 individuals genetically in one-sample Mendelian randomization analyses using five genetic variants. In the HERMES, UK Biobank, The Nord-Trøndelag Health Study (HUNT), deCODE, the Michigan Genomics Initiative (MGI), DiscovEHR, and the AFGen consortia, we performed two-sample Mendelian randomization analyses in up to 1,030,836 individuals using 12 genetic variants.

Results

In observational analyses, a 1 unit log-transformed higher plasma adiponectin was associated with a hazard ratio of 1.51 (95% confidence interval: 1.37–1.66) for heart failure, 1.63 (1.50–1.78) for atrial fibrillation, 1.21 (1.03–1.41) for aortic valve stenosis, and 1.03 (0.93–1.14) for myocardial infarction; levels above the median was also associated with increased risk of myocardial infarction. Corresponding genetic, causal risk ratios were 0.92 (0.65–1.29), 0.87 (0.68–1.12), 1.55 (0.87–2.76), and 0.93 (0.67–1.30) in one-sample Mendelian randomization analyses, while corresponding causal risk ratios were 0.99 (0.89–1.09), 1.00 (0.92–1.08), 1.01 (0.79–1.28), and 0.99 (0.86–1.13) in two-sample Mendelian randomization analyses, respectively.

Conclusions

Elevated plasma adiponectin was associated with increased risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction. However, genetic evidence did not support causality for those associations.

Background and Aims

Familial Hypercholesterolemia (FH) is suspected when LDL-C levels exceed the 95th percentile of the population distribution, but family and clinical history support the diagnosis. Different scoring systems have been developed, as the DLCN score, used worldwide to diagnose FH. The aim of the study is to describe the characteristics of FH patients of a large cohort of more than eight hundred genotyped subjects enrolled in an Italian Lipid Clinic and evaluated the DLCN score performance applied retrospectively.

Methods

836 hypercholesterolemic patients with LDL-C > 4.88 mmol/L were genotyped for FH causative mutations in the LDLR, PCSK and APOB genes. Relatives of mutated patients were also analyzed by cascade screening.

Results

Mutation carriers were younger, presented higher LDL-C and DLCN score and lower HDL-C levels in comparison with hypercholesterolemic (HC) noncarriers and presented a five-fold higher prevalence of previous CV events. Carotid US data available in 490 subjects, showed that mutation carriers had an odds ratio of 3.66 (1.43 – 10.24) for atherosclerotic plaques in comparison with noncarriers. Scoring system were evaluated by ROC analysis in 203 subjects without missing DLCN items and with available pre-therapy LDL-C levels, and LDL-C levels (A.U.C.=0.737) resulted more performing than the DLCN score (A.U.C.=0.662), even including carotid US data (A.U.C.=0.641) in a modified DLCN score version.

Conclusions

The DLCN scoring systems failed to demonstrate a clear superiority in predicting FH mutations in comparison with the measure of LDL-C levels in a retrospective case study. The results enforce the need for more performant tools to detect FH.

Background and Aims

To assess the efficacy and safety of lomitapide in paediatric patients with homozygous familial hypercholesterolaemia (HoFH).

Methods

APH-19 (NCT04681170) is an ongoing phase 3, open-label, single-arm trial of lomitapide in paediatric patients with HoFH receiving standard-of-care lipid-lowering therapy. The study consisted of a run-in period, followed by a 24-week efficacy phase, 80-week safety phase and follow-up period. Patients were stratified by age into three dose escalation groups: 5–10, 11– 15 and 16–17 years, where maximum daily doses were 20, 40 and 60 mg, respectively. Patients were titrated to maximum tolerated doses from a starting dose of 2 mg (patients 5–15 years) or 5 mg (16–17 years).

Results

Forty-three patients were treated (Female: 55.8%; mean age: 10.7 years). APH-19 met its primary endpoint; mean change from baseline LDL-C at Week 24 was -53.5% (95% CI -61.6 – -45.4, p<0.0001), with results similar between patients aged 5–10 and 11–17 (Figure 1). Mean reductions were also observed at Week 24 for non-high-density lipoprotein C (-53.9%; 95% CI -61.7 – -46.1, p<0.0001), total cholesterol (-50.1%; 95% CI -57.6 – -42.5, p<0.0001) and very-low-density lipoprotein cholesterol (-50.2%; 95% CI -59.1 – -41.2, p<0.0001).

Patients reported mild (48.8%), moderate (30.2%) and severe (11.6%) adverse events (AEs). One patient experienced a life-threatening AE (MACE; treatment unrelated). No serious AEs led to discontinuation.

Conclusions

In this study, lomitapide significantly reduced LDL-C levels in paediatric HoFH patients. Safety was consistent with the known profile of lomitapide, with no new signals identified.

Figure 1: Mean (SD) change from baseline LDL-C (mg/dL) Week 24

Background and Aims

Familial Hypercholesterolaemia (FH) is an inherited disease of high LDL-cholesterol caused by defects in LDLR, APOB and PCSK9 genes. A pathogenic variant cannot be found in ~60% of patients with clinical FH phenotype. Here we looked for genome-wide association with mutation-negative FH in a large UK cohort with whole genome sequencing (WGS).

Methods

WGS data from the 100,000 Genomes Project (100KGP) participants was generated by Genomics England. These included a cohort of 544 FH patients diagnosed using the Simon Broome criteria. Mixed model single variant analysis between 404 mutation-negative unrelated FH cases and 50,791 control participants of the 100KGP was run using high coverage WGS data.

Results

A single rare non-coding variant (rs140570886, gnomAD MAF= 0.02) in the LPA gene was significantly associated (p=1.73x10^-8) with unexplained FH. Two FH cases were homozygous and 33 heterozygous for the LPA variant. Several other suggestive associations were found (Figure 1).

Figure 1. Manhattan plot of GWAS of mutation-negative FH in the 100KGP. Genes in red had been previously associated with LDL-cholesterol.

Conclusions

Recent reports suggest that high Lp(a) concentrations, which are largely genetically determined, mimic clinical FH. Our findings support the idea that both Lp(a) and LDL-C measurements should be included in the differential diagnosis of FH. While CVD risk will be reduced by LDL-C reduction in individuals with either high Lp(a) or high LDL-C, available specific therapies to lower Lp(a) should be targeted to those who will benefit most.

Acknowledgement: This research was made possible through access to the data and findings generated by the 100,000 Genomes Project

Background and Aims

Aim: The ATP citrate lyase inhibitor, bempedoic acid, has been demonstrated to reduce low-density lipoprotein (LDL) cholesterol, but is effect on cardiovascular outcomes has not been previously studied.

Methods

Methods: 13,970 patients at high cardiovascular risk, LDL-C >100 mg/dL and documented statin intolerance were treated with bempedoic acid 180 mg or matching placebo daily for at least 24 months. The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization.

Results

Results: Bempedoic acid produced greater lowering of LDL-cholesterol (21.1 vs 0.6) from a baseline of 139 mg/dL. Less primary endpoint events were observed in the bempedoic acid group (11.7 vs 13.3%, hazard ratio (HR) 0.87, 95% CI 0.79 to 0.96, P=0.004). Bempedoic acid treated patients also demonstrated a lower rate of (1) the composite of cardiovascular death, myocardial infarction or stroke (8.2 vs 9.5%, HR 0.85, 95% CI 0.76 to 0.96, P=0.006), (2) myocardial infarction (3.7 vs 4.8%, HR 0.77, 95%, CI 0.66 to 0.91, P=0.002) and (3) coronary revascularization (6.2 vs 7.6%, HR 0.81, 95% CI 0.72 to 0.92, P=0.001). No difference was observed between groups with regard to myalgia (5.6 vs 6.8%), while bempdoic acid treated patients were more likely to experience gout (3.1% vs. 2.1%), cholelithiasis (2.2% vs 1.2%), and small increases in serum creatinine, uric acid and hepatic enzymes.

Conclusions

Conclusions: Lowering levels of LDL-cholesterol with bempedoic acid associated with reductions in the rate of cardiovascular events in patients with statin intolerance.

Background and Aims

Background: Lerodalcibep (LIB), a small recombinant fusion protein of a PCSK9-binding domain (adnectin) and albumin, demonstrated highly effective PCSK9 and LDL-C suppression in Phase 2 studies. This global Phase 3 trial included India and Turkey, evaluated safety and efficacy of LIB 300 mg SC QM compared to evolocumab (EVO) 420 mg SC QM in genetically confirmed HoFH patients with novel variants on stable lipid lowering therapy not receiving LDL-apheresis.

Methods

Methods: Eligible patients (age ≥10 years) were randomized to either LIB or EVO for 24 weeks (Period A) followed by an 8 week ‘washout’ and crossed over to the alternate therapy for the next 24 weeks (Period B).

Results

Results: Of 82 HoFH patients screened, 65 entered Period A and 56 completed both Periods (mean age 29; range 10-58 years; 45% male; mean baseline LDL-C 401 mg/dL); Mean (SD) reduction in LDL-C was -9.6% (24.3) on LIB and -11.7% (27.4) on EVO. LDL-C reductions were highly variable but were similar with LIB and EVO in individual subjects (r=0.79; p<0.001) - figure. Mean free PCSK9 levels were decreased by 81% at trough on LIB. Both drugs were well tolerated, with no treatment related safety concerns or deaths.

Conclusions

Conclusions: LIBerate-HoFH is the largest randomized and diverse global trial conducted in genetically confirmed HoFH patients. Despite robust PCSK9 suppression, the LDL-C response was highly variable but similar with both drugs. PCSK9 inhibitors remain standard of care in HoFH with good residual LDLR activity and worth assessing for those with novel variants but unknown LDLR activity.