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Evidence from epidemiologic as well as Mendelian randomization studies is in favor of an independent and causal association of high lipoprotein(a) (Lp(a)) concentrations with atherosclerotic cardiovascular disease (ASCVD) and cardiovascular mortality. Lipoprotein apheresis (LA) is an effective option for lowering plasma concentrations of atherogenic lipoproteins. High Lp(a) associated with clinically progressive ASCVD was approved as an indication for regular LA with reimbursement in 2008. To become eligible, the Lp(a) concentration should exceed 60 mg/dl or as equivalent 120 nmol/l, LDL-C concentration should be in normal range, i.e. close to current treatment targets with maximally tolerated lipid lowering medication, and ASCVD should be progressive despite optimal treatment of all other cardiovascular risk factors.

The protocol for a randomized controlled trial to investigate efficacy of LA in such patients had been proposed, but had not received ethical approval in Germany. Therefore, the observational Pro(a)LiFe multicenter study enrolled 170 consecutive patients with high Lp(a) and progressive ASCVD as required for approval of reimbursement to analyse the long-term effect of LA on mean annual ASCVD event rates. Pro(a)LiFe patients were finally investigated after completion of 12 years of regular LA. ASCVD events per 100 patient years were compared to a UK-Biobank cohort (UKBBC) with essentially identical ethnicity, incident ASCVD, and verified impact of elevated Lp(a) on ASCVD risk as published by the study group of Welsh et al.. The Pro(a)LiFe cohort was compared to corresponding clinical trajectories of the UKBBC subgroups stratified by low (6 [3-12] mg/dl ; 12 [5.7-25.4] nmol/l) and high Lp(a) concentrations (98 [81-120] mg/dl ; 209.9 [174.6-258.6] nmol/l). The high-concentration subgroup was essentially identical to the Pro(a)LiFe cohort (104 [81-130] mg/dl; 224 [174-278] nmol/l).

Patients were investigated retrospectively over a 5-year period before initiation of regular LA, prospectively 5 years after commencing LA, and again retrospectively until completion of 12 years of LA comprising a total trajectory of 17 years. 154 patients (90.6%) completed 5 years follow-up, 129 patients (75.9%) were available in year 12. A rapid, significant, clinically relevant and sustained reduction in the mean annual rate of cardiovascular events per patient was observed from y-5 to y-1 (0.27±0.25) versus y+1 until y+12 (0.06±0.08) (p<0.001).

The Pro(a)LiFe cohort exhibited very high mean event rates per 100 patient years regarding cardiovascular events one year before commencing LA, which for the primary composite of MACE plus ischemic stroke (IS) and for coronary revascularization was significantly higher compared to both UKBBC subgroups one year after the first ASCVD event. This demonstrated the exceptional selectivity of the Pro(a)LiFe cohort. After one year of LA treatment Pro(a)LiFe patients exhibited in all disaggregated parameters significantly lower event rates compared to one year before, which for the primary composite of MACE including IS and for nonfatal MI was significantly lower compared to both UKBBC subgroups one year after the first ASCVD event. An essentially identical pattern, but less pronounced than one year before, was seen when comparing the 5-year period after commencing LA with the corresponding median follow-up of 4.7 years after the first ASCVD event in the UKBBC.

Results support the clinical efficacy of LA to bring progressive ASCVD associated with high Lp(a) to a halt. While not replacing a true control group, the comparison with the UKBBC can help fill part of the scientific knowledge gap caused by the lack of a control group and strengthen existing evidence of LA's clinical efficacy in preventing cardiovascular events associated with high Lp(a). The association of elevated Lp(a) with increased rate of subsequent cardiovascular events has highlighted a high-risk population that may benefit from earlier and more targeted intervention for Lp(a) and other cardiovascular risk factors.

References:

Klingel et al. Lipoprotein apheresis for lipoprotein(a)-associated progressive atherosclerotic cardiovascular disease: 12-years follow-up. Atherosclerosis 2025;410:120508.

Leebmann et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicentre study. Circulation 2013;128:2567-2576.

Roeseler et al. Lipoprotein apheresis for lipoprotein(a)-associated cardiovascular disease: prospective 5 years of follow-up and apolipoprotein(a) characterization. Arterioscler Thromb Vasc Biol 2016;36:2019-2027.

Welsh P, Zabiby AA, Byrne H, et al. Elevated lipoprotein(a) increases risk of subsequent major adverse cardiovascular events (MACE) and coronary revascularization in incident ASCVD patients: a cohort study from the UK Biobank. Atherosclerosis 2024;389:117437.

Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by extreme hypertriglyceridemia and recurrent acute pancreatitis (AP). While volanesorsen is approved by the European Medicine Agency (EMA) for treatment of FCS, olezarsen, a new apolipoprotein C-III (apoC-III) inhibitor with a longer dosing interval and potentially improved safety profile, has been approved by both the Food and Drug Administration and the EMA. This analysis compared the efficacy and safety of olezarsen versus volanesorsen.

Objective: To indirectly compare the efficacy and safety of olezarsen 80 mg Q4W and volanesorsen 300 mg QW in pivotal phase 3 trials among adults with FCS using an MAIC.

Methods: An anchored MAIC was performed using individual patient data from Balance (NCT04568434; olezarsen, placebo) weighted to match baseline characteristics from APPROACH (NCT02211209; volanesorsen, placebo). Matching variables included fasting triglycerides (TG) and other treatment effect modifiers with significant (p < 0.05) or exploratory (p < 0.20) treatment-by-covariate interactions (variables considered were age, sex, body-mass index, race, and 5-year AP history). Post-weighting, outcomes were compared at 26 and 52 weeks for mean percent change in fasting TG, apoC-III, and for risk of AP and adverse events (AEs). Sensitivity analyses were conducted without matching to assess the impact of the matching procedure, and sensitivity MAICs were conducted with different sets of matching variables to assess the robustness of the results to different choices of covariates.

Results: The MAIC included 22 patients receiving olezarsen and 23 receiving placebo in Balance, and 33 patients receiving volanesorsen and 33 receiving placebo in APPROACH. After weighting, patient characteristics were well balanced between Balance and APPROACH, and the effective sample size for the entire Balance trial ranged from 33.6 to 41.0 depending on the outcome.

At 26 weeks, reduction in fasting TG was greater for volanesorsen (mean difference [MD] for olezarsen vs. volanesorsen: 17.9 %-points; 95% CI: −20.0, 55.8; not significant), whereas reduction in apoC-III was similar for both therapies (MD: −2.6 %-points; 95% CI: −28.3, 23.2). Both studies imputed missing long-term data (1 placebo patient discontinued in each study, while 3 and 14 patients discontinued in the studies’ olezarsen and volanesorsen arms, respectively). At 52 weeks, olezarsen showed greater reduction in fasting TG versus volanesorsen (MD: −27.5 %-points; 95% CI: −69.4, 14.5) and greater reduction in apoC-III (MD: −21.3 %-points; 95% CI: −61.9, 19.2), though differences were not statistically significant. Olezarsen was associated with a 77% lower risk of ≥1 AP event (risk ratio [RR]: 0.23; 95% CI: 0.01, 5.02) and 94% fewer AP events per patient-year (incidence rate ratio : 0.06; 95% CI: 0.003, 1.41) compared with volanesorsen, as well as lower risk of serious AEs (RR: 0.50; 95% CI: 0.08, 3.26) and treatment-related AEs (RR: 0.52; 95% CI: 0.16, 1.70), however these differences were not statistically significant. Sensitivity analyses yielded consistent results, supporting the primary results.

Conclusions: In this indirect comparison, olezarsen was associated with numerically greater reductions in fasting TG and apoC-III and lower risks of AP and AEs compared with volanesorsen over 52 weeks, though differences were not statistically significant. These results support olezarsen as a therapeutic option for patients with FCS and may represent a viable alternative for individuals currently receiving volanesorsen.

Sponsorship: Analysis funded by Ionis. Publication funded by Sobi.

Aim: Patients affected by severe hypertriglyceridemia currently have limited therapeutic options. Olezarsen is an antisense oligonucleotide, which lowers triglycerides reducing the hepatic synthesis of apolipoprotein C-III. The aim of this case report is to describe the clinical response to olezarsen in a patient with severe hypertriglyceridemia and poor control under standard-of-care therapy, causing recurrent pancreatitis.

Methods: We describe the case of a 63-year-old patient affected by severe hypertriglyceridemia and pancytopenia, carrying a pathogenic variant of LPL combined with a variant of unknown significance. The patient was initially enrolled in the clinical study Core, during which she received placebo and was observed throughout the study period. Subsequently, during the open-label extension phase, she was dosed with Olezarsen 80 mg. Clinical and biochemical parameters were monitored during both phases to assess changes in disease activity, safety, and treatment response.

Results: During placebo exposure, the patient experienced recurrent pancreatitis (3 episodes in 6 months), additionally to the 14 episodes reported in her medical history. After initiation of olezarsen, a clinically significant reduction in triglycerides levels could be observed, together with a prevention of pancreatitis episodes, and an unexpected improvement of the pancytopenia. No treatment-limiting adverse events were observed.

Conclusions: This case report suggests that olezarsen may represent a life-changing therapeutic option for patients with severe hypertriglyceridemia inadequately controlled with standard-of-care treatment. The marked biochemical and clinical improvements observed support further treatment and evaluation of medications targeting APO-C III in patients with similar clinical and biochemical profiles.

Background: GLP-1 and GLP-2 (glucagon-like peptide-1/2) are incretin hormones which are secreted in the gastrointestinal tract following food intake. GLP-1 and GLP-1 receptor agonists (GLP-1RA) have been extensively studied for their glucose-lowering, weight-reducing and cardioprotective pleiotropic effects, highlighting a mechanistic link in the gut–heart axis. In contrast, GLP-2 does not stimulate insulin secretion, but enhances gut barrier function. In clinical practice, GLP-2RA are indicated in patients with short-bowel syndrome. However, the role of GLP-2 for cardiovascular disease (CVD) is largely unknown.

Methods: Circulating GLP-2 levels were assessed in 539 hospitalized patients which were over the age of 50, fasted and had established atherosclerotic cardiovascular disease (ASCVD). The primary endpoint of this analysis was CV death. Associations of GLP-2 levels with the primary outcome were assessed with Kaplan-Meier curve and uni- and multivariable Cox proportional hazard regression analyses.

Results: Median GLP-2 levels of the cohort were 3.24 ng/mL. Over a median observation time of two years, CV death occurred in 31 out of 539 subjects. Kaplan Meier curve analyses demonstrated that individuals with GLP-2 levels above the median had a higher rate of CV death than those below the median (log-rank p=0.016). In univariable Cox regression analyses, continuous GLP-2 levels were significantly associated with CV death (Hazard ratio (HR): 1.31; 95% confidence interval (CI): 1.12, 1.52; p<0.001). Moreover, the association between GLP-2 and CV death remained significant in different multivariable models. In model 1 adjusted for age and sex (HR: 1.30; 95% CI: 1.12, 1.52; p<0.001), in model 2 adjusted for low-density lipoprotein cholesterol, high-sensitivity C-reactive protein and lipoprotein (a) (HR: 1.31; 95% CI: 1.12, 1.54; p<0.001) and in model 3 adjusted for N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate and total bilirubin (HR: 1.32; 95% CI: 1.13, 1.54; p<0.001) GLP-2 was independently associated with CV death. In model 4, which included standard modifiable risk factors (SMuRF: hypertension, dyslipidemia, type 2 diabetes and smoking) as covariables, this association persisted (HR: 1.20; 95% CI: 1.01, 1.42; p=0.042).

Conclusions: In hospitalized patients with established ASCVD elevated circulating GLP-2 levels were independently associated with CV death. Future studies are needed to investigate whether GLP-2 could be a novel CV risk marker and potential therapeutical target for CVD.

Introduction

Persistent chylomicronemia confers an increased risk of acute pancreatitis (AP). Chylomicronemia-associated AP is a substantial source of morbidity, mortality, reduced quality of life and financial burden to health care systems. Currently available therapies are often insufficient to reduce triglycerides (TG) and prevent AP. Plozasiran, an investigational siRNA, inhibits hepatic production of apolipoprotein C3 (APOC3), a key regulator of lipoprotein lipase-mediated TG metabolism and clearance. In a phase 2 study of severe hypertriglyceridemia (sHTG) patients, TG 500-4000 mg/dL, plozasiran demonstrated durable reductions in TG levels of approximately -80%, 12 weeks after the last dose, and in the majority of patients decreased circulating TG below 500 mg/dL, the threshold for increased risk for AP, with a numerical decrease in incidence of AP of 82% with a similar magnitude of reduction in AP achieving significance in the phase 3 PALISADE study of FCS. The SHASTA-5 trial will evaluate efficacy of plozasiran for reduction in AP rates, in patients with sHTG at high risk of AP.

Methods

SHASTA-5 is a randomized, double-blind, placebo-controlled, multi-center trial. Key inclusion criteria are 2 consecutive mean fasting TG level ≥ 1000 mg/dL and at least 2 prior documented AP events not attributed to other causes, one within 12-months from screening. Key exclusion criteria include use of any hepatocyte targeted siRNA treatments that target lipids and/or TGs within 1-year, and a screening HbA1c > 9.0%. Patients will agree to dietary counseling, maintaining a stable low-fat diet and receiving lipid-lowering medications throughout the study.

Results

In this global time-to-first event study, approximately 140 patients will be randomized 1:1 to receive plozasiran 25 mg subcutaneous dose quarterly or matching placebo over the double-blinded period with maximum expected follow up of 3 years followed by an optional open label extension. Randomization will be stratified based on number of documented AP events within 1-year of screening and baseline TG levels (≥ 2000 mg/dL vs < 2000 mg/dL). The primary efficacy endpoint is time-to-first occurrence of positively adjudicated AP events. Secondary endpoints include percent change in fasting TG from baseline to month-12 with plozasiran; proportion of patients who achieve fasting TG of <880 mg/dL; achievement of fasting TG of < 500 mg/dL; time to first major abdominal pain event occurring; and change from baseline in patient-reported productivity and activity impairment (WPAI-SHP score) and health status (EQ-5D-5L score).

Conclusions

SHASTA-5 is designed to determine whether the quarterly-dosed APOC3 siRNA plozasiran safely reduces the rate of AP in patients with sHTG.

Background:

Acute myocardial infarction (AMI) is a leading cause of worldwide mortality. Acute occlusion of a coronary artery results in myocardial ischemia followed by cardiomyocyte death, triggering local inflammation. While inflammatory processes contribute to the expansion of tissue injury and adverse cardiac remodeling, they are also essential for cardiac wound healing. These processes are driven by various immune cells, membrane-bound receptor-ligand dyads and cytokines, which regulate pro-inflammatory and regulatory intracellular signaling pathways. The pathophysiology of AMI is significantly influenced by cardiovascular risk factors like type 2 diabetes (T2D). Diabetic patients generally have a worse outcome after AMI, which is partly attributed to chronic inflammation. Among the key immunomodulatory signaling system, the co-stimulatory receptor-ligand dyad CD40–CD40L plays a pivotal role in both innate and adaptive immune response by regulating T-cell function, macrophage activation and immune cell differentiation, proliferation and survival. Previous studies have demonstrated an important role of CD40–CD40L interaction in processes involved in AMI and myocardial wound healing. Increased CD40–CD40L activity – also observed in diabetic patients – was associated with adverse cardiac outcome. However, the dynamics of CD40–CD40L and other, potentially associated, intercellular signaling molecules following AMI remain partially understood and require further investigations.

Methods:

Plasma levels of soluble (s) CD40, sCD40L, CD27 and various cytokines were determined in patients with ST-segment elevation myocardial infarction (STEMI) using NULISA-Seq (n = 44) and Luminex (n = 19) multiplex assays. Development of plasma levels during the first 24 hours after STEMI and differences between patients with and without T2D were analyzed using 2way ANOVA with repeated measurements and Sidak’s multiple comparisons test. Correlation between plasma level changes were determined using Pearson correlation analysis.

Results:

During the first 24 hours after STEMI, a general downregulation of intercellular signaling molecules (such as sCD40L, interleukin (IL)-4, IL-7, IL-10 and IL-18) was observed in NULISA analysis, while sCD40 plasma levels showed no significant alteration. Downregulation was attenuated in diabetic patients, with sCD40 plasma levels showing a tendency to increase and sCD40L plasma levels decreasing less in patients with than in patients without T2D. Luminex analysis showed more ambiguous results while still supporting some findings of the NULISA analysis, such as downregulation of sCD40L and IL-7. Correlation analysis of plasma level changes in the first 24 hours after STEMI showed correlation between CD40 and sCD40L in NULISA analysis. Furthermore, both NULISA and Luminex analysis showed strong correlations between the CD40–CD40L dyad and both IL-7 and IL-18 in diabetic and non-diabetic patients.

Conclusion:

Diabetic patients show signs of prolonged inflammation after STEMI with attenuated downregulation of intercellular signaling molecules, while indicating a larger role of CD40–CD40L interaction in post-ischemic mechanisms compared to non-diabetic patients. Correlation analysis points to possible co-regulation of CD40–CD40L and both IL-7 and IL-18 after AMI.