👤 Sotirios Tsimikas

Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL cholesterol (LDL-C), and reduces apolipoprotein B (apoB) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. We conducted a coronary computed tomography angiography (CCTA) study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen vs. placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence or high risk for cardiovascular disease, and non-calcified plaque on baseline CCTA. The primary endpoint was percent change from baseline to 12 months in non-calcified plaque volume (NCPV). Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (IQR 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (IQR 197-331), and remnant cholesterol was 53 mg/dL (IQR 38-76). Median baseline NCPV was 125.3 mm Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. Show less

Oxidative modification of apolipoprotein B-100 (apoB) containing particles and subsequent immune responses contribute to the pathogenesis of atherosclerosis. Circulating IgG and IgM apoB-containing immune complexes (apoB-IC) and autoantibodies to a malondialdehyde mimotope (anti-MDA-mimotope) serve as biomarkers of oxidative stress and immune activation in atherosclerotic cardiovascular disease. Elevated lipoprotein(a) [Lp(a)] is associated with increased oxidative burden and immune activation. To investigate the effect of lipid-lowering medications on IgG and IgM apoB-IC and IgG and IgM autoantibodies to an MDA-mimotope in individuals with elevated lipoprotein(a) [Lp(a)] concentrations. In this prospective study, patients (n = 70) with Lp(a) levels ≥ 75 nmol/L were assigned to 3 treatment regimens according to current guidelines: high-intensity statin monotherapy (n = 28), ezetimibe added to high-intensity statin (n = 31) and proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) added to high-intensity statin plus ezetimibe (n = 11). IgG and IgM apoB-IC and IgG and IgM anti-MDA-mimotope were measured at baseline and 3 months after treatment initiation. Patients had a mean age of 51 ± 15 years and 40% were male. Significant reductions in IgG apoB-IC levels were observed following treatment with high-intensity statins, add-on ezetimibe and add-on PCSK9i (by 18.3%, 17.5% and 25.5%, respectively, all p < 0.05). No significant changes in IgM apoB-IC, or IgG and IgM anti-MDA-mimotope levels were observed in any treatment group. In individuals with Lp(a) levels ≥ 75 nmol/L, high-intensity statins, add-on ezetimibe and add-on PCSK9i reduced IgG apoB-IC but did not affect IgM apoB-IC, or IgG and IgM anti-MDA-mimotope levels. The clinical significance of these findings warrants further investigation. Show less

Oxidized phospholipids (OxPL) are bioactive lipid species that circulate bound to apolipoprotein B-100 [apoB] and apolipoprotein(a) [apo(a)] and have been widely studied as biomarkers of oxidative lipid burden. When bound to apolipoprotein B-100 [OxPL-apoB] and apolipoprotein(a) [OxPL-apo(a)], they serve as informative biomarkers for CVD risk prediction, risk reclassification, and therapeutic monitoring, particularly in studies involving RNA-targeted therapies against lipoprotein(a). To date, measurement of OxPL-apoB and OxPL-apo(a) has been limited to research-use assays performed in an academic laboratory without formal clinical laboratory validation. Here we report the first full CLIA-compliant analytical validation of chemiluminescent ELISA methods for OxPL-apoB and OxPL-apo(a), enabling their implementation in a regulated clinical reference laboratory setting. The OxPL-apoB ELISA employs murine monoclonal IgG antibody MB47 to capture apoB-100-containing lipoproteins, while the OxPL-apo(a) employs murine monoclonal IgG antibody LPA4 to capture apo(a)-containing particles. In both assays, OxPL is detected by murine monoclonal IgM antibody biotin-E06. The concentration of OxPL is determined against a standard curve of phosphocholine (PC) equivalents using PC-modified bovine serum albumin. The analytical measuring range of both assays is 1.48-148.48 nmol/L PC-OxPL. Serum and plasma matrices showed minimal bias and were analytically equivalent. In healthy donors, OxPL-apoB levels ranged from <1.48 to 25.23 nmol/L PC-OxPL (mean 4.18, median 1.79 nmol/L), while OxPL-apo(a) levels ranged from <1.48 to 126.94 nmol/L PC-OxPL (mean 31.04, median 6.90 nmol/L), with strong correlation to Lp(a) concentrations (R Show less

Familial chylomicronemia syndrome (FCS) is a rare genetic disorder associated with extreme hypertriglyceridemia and high risk of acute pancreatitis. Olezarsen-an antisense oligonucleotide targeting hepatic apolipoprotein C3 (APOC3) messenger RNA-reduces triglycerides and may decrease pancreatitis risk. Olezarsen 80 mg once monthly is approved in the United States as an adjunct to diet to reduce triglycerides in adults with FCS. To assess the effect of olezarsen on all-cause healthcare resource utilization (HCRU) and overall experience of patients with genetically identified FCS enrolled in the Balance trial (NCT04568434). Prespecified exploratory endpoints included yearly all-cause hospitalization, total inpatient days, and emergency room visits for patients treated with olezarsen (80 or 50 mg) vs placebo, as well as Patient Global Impression of Change (PGIC). Ad hoc outcomes included length of hospital stay, intensive care unit (ICU) admissions, reasons for HCRU, and all-cause HCRU according to patients' history of acute pancreatitis and for individual olezarsen doses vs placebo. Treatment with olezarsen vs placebo for 1 year was associated with an 84% reduction in all-cause hospitalizations (mean rate ratio [95% CI], 0.16 [0.05, 0.50]), 6.3 fewer total inpatient days (95% CI, -11.09, -1.53), better PGIC scores, shorter length of stay, and numerically fewer ICU admissions. Acute pancreatitis was the most frequent cause of hospitalization. Reduction in all-cause inpatient service utilization was consistent for individual dose groups and in patients with a history of acute pancreatitis. In the Balance study, olezarsen reduced all-cause inpatient service utilization and improved the experience of patients with FCS. Show less

Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular disease, but its impact on long-term coronary plaque progression remains unclear. This study synthesizes evidence from CCTA, IVUS, and OCT to clarify the relationship between high-risk Lp(a) and coronary plaque burden and high-risk plaque features. We conducted a comprehensive search of multiple databases up to July 2025 for studies evaluating Lp(a) and atherosclerotic plaque progression. Statistical analysis was performed using a random-effects model in RevMan 5.4, reporting odds ratios (OR) and mean differences (MD) with 95% confidence intervals (CI). The protocol is registered in PROSPERO (CRD420251113955). Our final analysis included 16 studies comprising 19,822 participants with a mean age of 62 years and a median imaging follow-up ranging from 10 months to 10.2 years. On analysis, high-risk Lp(a) levels were significantly associated with the presence of coronary plaque (OR 1.53; 95% CI, 1.03-2.29; p = 0.04) compared with low Lp(a) levels. Additionally, patients with elevated Lp(a) exhibited significantly greater progression in percent atheroma volume (ΔPAV) than those with low levels (MD 4.31%; 95% CI, 1.08-7.53; p = 0.009). Subgroup analysis by plaque phenotype revealed a statistically significant increase in low-attenuation plaque (LAP) presence among individuals in the high-risk Lp(a) category (OR 1.92; 95% CI, 1.13-3.27; p = 0.02). High-risk Lp(a) is associated with greater coronary plaque prevalence, accelerated progression, and increased LAP. These findings underscore Lp(a) as a driver of high-risk, rupture-prone plaques and a critical biomarker and potential therapeutic target in cardiovascular risk management. Show less

Accurate measurement of lipoprotein(a)-cholesterol [Lp(a)-C] may be useful in interpreting the traditional lipid panel, particularly in patients with high Lp(a). We developed and analytically validated a direct immunocapture ELISA in a Clinical Laboratory Improvement Amendments-certified laboratory for quantifying Lp(a)-C in human plasma using an apolipoprotein(a)-specific monoclonal antibody (LPA4) coupled to magnetic beads. The linearity of the assay was found to be excellent (R Show less

Lipoprotein(a) [Lp(a)] and LDL cholesterol (LDL-C) are causally linked to aortic valve calcium (AVC) and aortic stenosis (AS). Lipoprotein(a) has anti-fibrinolytic properties; therefore, aspirin may reduce cardiovascular disease risk among individuals with high Lp(a). This analysis sought to determine the association of aspirin with incident AVC and AS across Lp(a) and LDL-C levels. This observational study included up to 6598 participants in the Multi-Ethnic Study of Atherosclerosis. Aortic valve calcium was measured on non-contrast cardiac computed tomography. Multivariable Cox hazards regression assessed the association of self-reported regular aspirin use (≥3 days/week) with incident AVC and severe AS, stratified by Lp(a) and LDL-C. Aortic valve calcium and Lp(a) values were not reported to participants. Mean age was 62 years, 53% were women, 23% reported regular aspirin use, 8% developed AVC (median 8.9 years), and 1% developed severe AS (median 16.7 years). Among individuals with elevated Lp(a), regular aspirin use was associated with a lower risk of incident AVC (Lp(a) ≥75 mg/dL: hazard ratio (HR) .42, 95% confidence interval (CI) .19-.93; Lp(a) ≥100 mg/dL: HR .17, 95% CI .04-.67) and severe AS (Lp(a) ≥50 mg/dL: HR .13, 95% CI: .04-.47; Lp(a) ≥75 mg/dL: HR .02, 95% CI .001-.29). For participants with elevated LDL-C, there was no association of regular aspirin use with incident AVC (LDL-C ≥130 mg/dL: HR 1.02, 95% CI .66-1.58; LDL-C ≥160 mg/dL: HR 1.51, 95% CI .53-4.28) or severe AS (LDL-C ≥100 mg/dL: HR .70, 95% CI .39-1.26; LDL-C ≥130 mg/dL: HR .46, 95% CI .14-1.47). In this exploratory analysis of prospective observational cohort data, regular aspirin use was associated with a lower risk of AVC and severe AS in persons with high Lp(a), but not high LDL-C. Confirmatory studies are required to determine the role of aspirin in the prevention of AVC and AS for persons with high Lp(a). Show less

Lp(a) (lipoprotein[a]) is a known cardiovascular risk factor; however, its role in cardiac remodeling and functional changes over time across diverse racial and ethnic groups remains underexplored. MESA is a prospective multi-ethnic cohort study of individuals without a history of cardiovascular disease on enrollment (2000-2002), conducted across 6 sites in the United States. Participants with baseline Lp(a) measurements and cardiac magnetic resonance imaging at both baseline and 10-year follow-up exam were included. Lp(a) was treated as both a log-transformed continuous variable (per SD log) and a categorical variable based on data-driven Lp(a) terciles. Multivariable regression models adjusted for sociodemographic, and cardiovascular risk factors, including coronary artery calcium and interim myocardial infarction, were used to assess associations between Lp(a) and longitudinal changes in left ventricular and atrial structure and function over a decade across different racial/ethnic groups. A total of 2366 participants were included. The average age at baseline was 60±9 with 53% women, 43% White, 24% Black, 21% Hispanic, and 12% Chinese. Each 1-SD increase in log-transformed Lp(a) was associated with an increase in left ventricular end-systolic volume index (β, 0.60 [95% CI, 0.02-1.18]), and left atrial minimum volume index (β, 0.81 [95% CI, 0.09-1.52]), and a decline in left ventricular ejection fraction (β, -0.75 [95% CI, -1.34 to -0.17]), and total left atrial emptying fraction (β, -1.17 [95% CI, -2.09 to -0.24]) in Hispanic subjects over a decade. No significant associations were seen in White, Black, or Chinese participants. The observed findings persisted after adjusting for coronary artery calcium, interim myocardial infarction, and atrioventricular decoupling, and when Lp(a) was treated as a categorical variable with race-specific terciles. Elevated Lp(a) levels were independently associated with maladaptive left ventricular and left atrial remodeling in Hispanic adults over a decade, while no statistically significant relationships were observed in White, Black, and Chinese participants. This suggests a unique susceptibility of Hispanic individuals to Lp(a)-mediated cardiovascular remodeling, independent of ischemic pathways. Show less

Lipoprotein (a) [Lp(a)] is viewed as a cholesterol-rich, LDL-like particle, yet potential heterogeneity in its lipid composition is not well understood. We developed and validated a novel immune-isolation assay to directly quantify triglycerides (TGs) associated with Lp(a) [Lp(a)-TGs]. Lp(a) was selectively isolated from plasma using magnetic beads conjugated with monoclonal antibody LPA4 targeting apolipoprotein(a), followed by enzymatic quantification of TGs. Assay specificity was ensured using washing buffers to prevent nonspecific lipoprotein interactions. Spike-in experiments with purified VLDL/intermediate density lipoprotein lacking Lp(a) demonstrated no measurable interference. Lp(a)-cholesterol [Lp(a)-C] was measured using an established immune-isolation method. The ratio of Lp(a)-TG to Lp(a)-C was calculated to distinguish TG-enriched Lp(a) particles from the typical cholesterol-rich, LDL-like phenotype. Lp(a)-TG, Lp(a)-C, Lp(a) molar concentration, and estimated compositional ratios were quantified in 36 normotriglyceridemic individuals and 114 individuals with moderate hypertriglyceridemia (150-500 mg/dl). In normotriglyceridemic individuals, mean (SD) TGs were 98.4 (31.9) mg/dl, Lp(a)-TG 1.42 (2.83) mg/dl, Lp(a)-C 4.03 (4.01) mg/dl, and the Lp(a)-TG/Lp(a)-C ratio was 0.59 (1.27). Lp(a)-TG and Lp(a)-C accounted for mean (SD) 1.22% (0.10) of total plasma TGs and 2.62% (2.01) of total plasma cholesterol. In individuals with hypertriglyceridemia, mean (SD) TGs were 284 (85) mg/dl, Lp(a)-TG 53.7 (25.3) mg/dl, Lp(a)-C 14.4 (6.9) mg/dl, and the Lp(a)-TG/Lp(a)-C ratio was 3.99 (1.20). Lp(a)-TG and Lp(a)-C accounted for mean (SD) 19.9% (6.53) of total plasma TGs and 9.68% (4.41) of total plasma cholesterol. This immune-isolation assay is the first validated, high-throughput method for direct quantification of Lp(a)-TG. This study demonstrates that Lp(a) lipid composition is variable and enriched in triglycerides and cholesterol in hypertriglyceridemic states. It provides a platform for future mechanistic, epidemiologic, and pharmacologic studies of Lp(a)-triglyceride interactions. This immune-isolation assay is the first validated, high-throughput method for direct quantitation of Lp(a)-TG. Show less

Familial chylomicronemia syndrome (FCS) is diagnosed by genetic or nongenetic criteria. To assess responses to treatment of apolipoprotein (apo)C-III, triglycerides, and pancreatitis events in patients with FCS-based diagnostic methods. APPROACH enrolled 66 patients with FCS randomized to volanesorsen or placebo for 12 months. In 50 participants, genetic confirmation of FCS was based on the presence of pathogenic bi-allelic variants in LPL, APOC2, APOA5, GPIHBP1, or LMF1 genes. In 16 participants without a genetic diagnosis, FCS was diagnosed using clinical criteria and postheparin lipoprotein lipase activity ≤20% of normal. Plasma levels of apoC-III, triglycerides and related variables were measured at 3, 6, and 12 months. No significant differences were present in mean apoC-III reductions with volanesorsen at 3, 6, or 12 months in patients with FCS diagnosed either genetically or nongenetically. In contrast, the triglyceride reductions were statistically less robust in patients with genetic diagnosis at each timepoint, with mean (95% CI) percent reduction in triglycerides of -68.7% (-78.7, -58.6) vs -84.0% (-99.4, -68.6), P = .014 at Month 3; -58.2% (-78.1, -38.2) vs -84.5% (-122.4, -46.7), P = .009 at Month 6; and -35.6% (-57.7, -13.4) vs. -69.0% (-105.0, -33.1), P = .005 at Month 12. Patients with a genetic diagnosis had significantly lower response rates for achieved triglycerides <500 mg/dL, <750 mg/dL, <880 mg/dL and <1000 mg/dL than patients with a nongenetic diagnosis. All 5 episodes of acute pancreatitis occurred in patients with a genetic diagnosis. For a similar reduction in apoC-III in response to volanesorsen, triglyceride reduction is attenuated in patients with genetically vs nongenetically diagnosed FCS. Show less

Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) reflect pro-inflammatory properties of Lp(a) (lipoprotein(a)). The effect of OxPL-apoB on major adverse cardiovascular events (MACE) in patients with acute coronary syndrome in recent the era is not known. OxPL-apoB levels and Lp(a) were measured in 11 630 participants before and 5185 participants 4 months after randomization to alirocumab or placebo in the ODYSSEY OUTCOMES trial. Proportional hazards models adjusted for baseline covariates evaluated associations between log Participants were followed for a median 2.9 years; the median age was 58 years, and 23.9% were female. Alirocumab reduced median placebo-adjusted OxPL-apoB by 13.0% and Lp(a) by 26.2% (both In patients with recent acute coronary syndrome receiving optimized statin treatment, elevated OxPL-apoB levels predicted MACEs, a relationship abrogated by alirocumab. The interaction of OxPL-apoB and Lp(a) in the placebo group indicates that OxPL-apoB independently predicts MACEs when Lp(a) levels are relatively low. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT001747 and NCT01663402. Show less

Oxidized phospholipids (OxPLs) are bound to apolipoprotein B-100 (OxPL-apoB) and apolipoprotein(a) [OxPL-apo(a)] and are present freely within the phospholipid shell of apoB-containing lipoproteins. OxPLs have been linked with the pro-inflammatory properties of lipoprotein(a) [Lp(a)]. OxPLs carried on plasminogen (OxPL-PLG) may extend the time to fibrinolysis. To evaluate the effect of lipid-lowering medications on OxPLs levels in individuals with elevated Lp(a) concentrations. In this prospective study, patients (n = 70) with Lp(a) levels ≥75 nmol/L were assigned to 3 treatment regimens according to current guidelines: high-intensity statin monotherapy (n = 28), ezetimibe added to high-intensity statin (n = 31) and proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) added to high-intensity statin plus ezetimibe (n = 11). Follow-up duration was 3 months. Patients had a mean age of 51 ± 15 years, 40 % were male, 39 % were diagnosed with familial hypercholesterolemia, 16 % had atherosclerotic cardiovascular disease, and 36 %, 33 % and 15 % were at very high, high, and moderate cardiovascular risk, respectively. Lp(a) levels did not change significantly with high-intensity statin and add-on ezetimibe but significantly decreased with add-on PCSK9i treatment. OxPL-apoB and OxPL-apo(a) significantly increased, while OxPL-PLG significantly decreased with both high-intensity statin and add-on ezetimibe. Add-on PCSK9i treatment was associated with no significant changes in OxPL-apoB, OxPL-apo(a) and OxPL-PLG levels. Among patients with elevated Lp(a), both high-intensity statin and add-on ezetimibe significantly increased OxPL-apoB and OxPL-apo(a) levels, while significantly decreased OxPL-PLG levels. Add-on PCSK9i had no significant effect on OxPLs levels. The clinical implications of these findings should be further explored. Show less

OxPL-apoB (oxidized phospholipids [OxPL] on apoB-100), which include OxPL present on Lp(a) (lipoprotein[a]), are associated with higher cardiovascular risk. Experimental studies suggest that OxPL may influence platelet function. This observational study assessed the association of OxPL-apoB with intrinsic and on‑clopidogrel platelet reactivity and long-term cardiovascular events in patients undergoing coronary angiography with or without percutaneous coronary intervention in 2040 patients in the EXCELSIOR trial (Impact of Extent of Clopidogrel-Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate). The association of OxPL-apoB to expression of CD62P, CD41, or PAC-1 levels and intrinsic and on-clopidogrel platelet reactivity to collagen and ADP was determined. The relationship of OxPL-apoB and Lp(a) to myocardial infarction-free survival and all-cause mortality at a median of 7 years was assessed using Cox regression models. Elevated levels of OxPL-apoB were associated with the severity of coronary obstruction, and higher prevalence of prior myocardial infarction, percutaneous coronary intervention, and coronary artery bypass graft surgery. No significant associations were present between OxPL-apoB and intrinsic or on-clopidogrel platelet reactivity or activation of platelet receptors. Analyzed individually in separate multivariable models, both OxPL-apoB (hazard ratio, 1.022 [95% CI, 1.005-1.040]; In patients undergoing coronary angiography with or without percutaneous coronary intervention, OxPL-apoB was not associated with intrinsic and on-clopidogrel platelet reactivity mediated by collagen or ADP. The association of OxPL-apoB and Lp(a) suggests that the accumulation of OxPL on Lp(a) may be a key determinant of long-term cardiovascular outcomes. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00457236. Show less

The peri- and early post-infarction period carries an increased risk of recurrent ischemic events. Oxidized phospholipids (OxPLs) are pro-inflammatory and contribute to plaque instability and thrombosis. This study aimed to: (1) assess changes, during the early post-MI period in OxPL-apo(a) and OxPL-apoB, (2) evaluate the effect of PCSK9 inhibition on these changes, and (3) explore their relationships with the changes in Lp(a) and LDL-C. Ninety-six participants with NSTEMI or STEMI were randomized to receive placebo (n = 48) or 420 mg subcutaneous evolocumab (n = 48) within 24 h of admission. OxPL-apo(a), OxPL-apoB, Lp(a), and LDL-C levels were measured at baseline and 30 days post-MI. In the placebo group, OxPL-apo(a) increased from 52.6 [19.3, 106.5] nmol/L at baseline to 61.7 [31.5, 116.9] nmol/L at 30 days (p = 0.014), and OxPL-apoB rose from 6.7 [3.1, 21] nmol/L to 8.8 [3.7, 23] nmol/L (p = 0.0045). In contrast, no significant changes were observed for OxPL-apo(a) (p = 0.17) or OxPL-apoB (p = 0.058) in the evolocumab group. OxPL-apo(a) correlated strongly with Lp(a) at baseline (r = 0.93, p < 0.001) and 30 days (r = 0.94, p < 0.001), and OxPL-apoB correlated similarly (baseline: r = 0.92, p < 0.001; 30 days: r = 0.93, p < 0.001). No correlation was observed between OxPLs and LDL-C. OxPL-apo(a) and OxPL-apoB levels were strongly correlated with Lp(a) and increased during the early post-infarction period. This increase was prevented by in-hospital administration of a PCSK9 inhibitor. These findings provide new insights into early changes in OxPLs following acute MI and suggest a protective role for PCSK9 inhibition during this critical period. Show less

Apolipoprotein C-III (apoC-III) is transported on chylomicrons, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipoprotein(a) [Lp(a)]. Olezarsen, a hepatic-targeted antisense oligonucleotide targeting APOC3 mRNA, lowers apoC-III and triglycerides and reduces pancreatitis events. This study evaluated the reduction of apoC-III in specific lipoprotein pools after treatment with olezarsen. Participants with familial chylomicronemia syndrome (FCS) in the Balance study received olezarsen 80 mg (n = 22), 50 mg (n = 21), or placebo (n = 23). Triglycerides, apoC-III, and lipoprotein-associated apoC-III was measured at baseline and days 85, 169, 253, and 365 using chemiluminescent ELISAs. Lipoprotein-associated apoC-III levels were measured in 4 lipoprotein pools, apoC-III-total apoB (apoB-48+apoB-100), apoC-III-apoA-I (HDL), apoC-III-apoB-100 (VLDL + LDL), and apoC-III-apo(a) (Lp(a)). The placebo-adjusted average percent changes from baseline to day 365 were calculated. The average percent changes from baseline to day 365 in apoC-III were -61.9 % and -74.7 % and for triglycerides -37.8 % and -55.7 % with olezarsen 50 mg and olezarsen 80 mg, respectively. The corresponding olezarsen-placebo average differences (95 % CI) in apoC-III-total apoB levels were -47.1 % (-64.1, -32.6) and -65.8 % (-81.5, -49.8), respectively and apoC-III-apoA-I by -53.6 % (-79.3, -29.4) and -76.1 % (-104.1, -55.4), respectively (p<0.001 for all). ApoC-III-apoB-100 was reduced by -12.5 % (-28.1, 2.1) (p = 0.0768) and -29.9 % (-46.1, -16.0) (p = 0.0006) and apoC-III-apo(a) by -15.7 % (-47.5, 10.6) (p = 0.18) and -39.1 % (-70.2, -16.1) (p = 0.0024), with olezarsen 50 mg and olezarsen 80 mg respectively. In adults with FCS, olezarsen significantly lowers apoC-III in all major lipoprotein pools, particularly in total apoB and apoA-I. Tracking changes in apoC-III among various lipoprotein pools elucidates the action of olezarsen on apoC-III and may inform future studies of pancreatitis and cardiovascular risk with apoC-III-targeted therapies. Show less

There is a need for effective tools to stratify and modify cardiovascular risk associated with elevated lipoprotein(a) [Lp(a)] and oxidized phospholipids (OxPL). The objective of this analysis was to explore the modifying effects of low-grade inflammation on Lp(a)- and OxPL-associated risk in a secondary prevention cohort. Levels of Lp(a), OxPL associated with apolipoprotein(a) (OxPL-apo[a]) and apolipoprotein B (OxPL-apoB) were determined in the placebo-arm of the low-dose colchicine 2 trial. Patients were between 35 and 82 years, had established chronic coronary syndrome (CCS), and were clinically stable for at least six months prior to randomization. The outcome was the incidence of the composite endpoint of spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization stratified by biomarker levels using a Cox regression model. There was a significant interaction between Lp(a) and IL-6 <3.2 ng/L (median) and IL-6 ≥3.2 ng/L for the composite endpoint (HR 0.90; 95 %CI 0.78-1.03 vs HR 1.18; 95 %CI 1.01-1.39, P In patients with CCS, Lp(a), OxPL-apo(a) and OxPL-apoB associated cardiovascular risk was only pertinent in those with elevated IL-6 but not hsCRP levels. Show less

Inflammatory lipoprotein(a) [Lp(a)] and oxidized phospholipids (OxPLs) on lipoproteins convey residual cardiovascular disease risk. The low-dose colchicine 2 (LoDoCo2) trial showed that colchicine reduced the risk of cardiovascular events occurring on standard therapies in patients with chronic coronary syndrome (CCS). We explored the effects of colchicine on Lp(a)- and oxidized lipoprotein-associated risk in a LoDoCo2 biomarker subpopulation. Lipoprotein(a) and OxPLs on apolipoprotein(a) [OxPL-apo(a)] and apolipoprotein B-100 (OxPL-apoB) levels were determined in the biomarker population of the LoDoCo2 trial (n = 1777). The Cox regression analysis was used to compare the risk of the primary endpoint, consisting of myocardial infarction, ischaemic stroke, or ischaemia-driven revascularization by biomarker levels. Interactions between treatment, Lp(a), and OxPL levels were evaluated. Lipoprotein(a), OxPL-apo(a), and OxPL-apoB levels were similar between the colchicine and placebo groups. Consistent risk reduction by colchicine was observed in those with Lp(a) < 125 nmol/L and ≥125 nmol/L and the highest OxPL-apo(a) tertile compared with the lowest (Pinteraction = 0.92 and 0.66). The absolute risk reduction for those with Lp(a) ≥ 125 nmol/L appeared higher compared with those with Lp(a) < 125 nmol/L (4.4% vs. 2.4%). A treatment interaction for colchicine was found in those with the highest OxPL-apoB tertile vs. the lowest (Pinteraction = 0.04). In patients with CCS, colchicine reduces cardiovascular disease risk in those with and without elevated Lp(a) but absolute benefits appeared higher in those with Lp(a) ≥ 125 nmol/L. Patients with higher levels of OxPL-apoB experienced greater benefit of colchicine, suggesting that colchicine may be more effective in subjects with heightened oxidation-driven inflammation. Show less

Apolipoprotein C-III (apoC-III) is a central regulator of triglyceride metabolism. Elevated triglyceride levels are associated with increased risk of acute pancreatitis and atherosclerotic cardiovascular disease (ASCVD). Conventional triglyceride-lowering therapies, such as fibrates and omega-3 fatty acids, have limited efficacy in reducing triglycerides and in reducing the risk of pancreatitis or ASCVD in patients with severe hypertriglyceridemia. ApoC-III inhibits lipoprotein lipase and impairs clearance of both triglyceride-rich and cholesterol-rich lipoproteins. Novel therapies targeting APOC3 mRNA to reduce triglycerides, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), achieve greater triglyceride reductions than standard agents. Volanesorsen and olezarsen, both ASOs, are approved as an adjunct to diet to reduce triglycerides in familial chylomicronemia syndrome (FCS) in different regions. Plozasiran, an siRNA, is in late-stage clinical development. Indirect cross-trial comparisons were performed, aligned by timepoint and outcome measures, and indicate comparable efficacy of olezarsen and plozasiran in patients with chylomicronemia. APOC3 inhibition is now an established therapeutic approach for reducing the risk of acute pancreatitis in FCS, with three agents, volanesorsen, olezarsen, and plozasiran, demonstrating efficacy. However, its role in ASCVD prevention remains unproven. This review evaluates current APOC3 - targeted therapies for FCS, including available comparative data, and synthesizes the emerging literature on the potential of APOC3 inhibition to reduce the burden of acute pancreatitis in broader populations with severe hypertriglyceridemia, as well as its potential role in ASCVD risk reduction. Show less

Highly effective therapies to reduce triglyceride levels are lacking. Olezarsen is an In this phase 3, international, double-blind, randomized, placebo-controlled trial, we enrolled patients with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) and randomly assigned them in a 1:3 ratio to a 50-mg or 80-mg cohort. The patients were then randomly assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the least-squares mean percent change in triglyceride level from baseline to 6 months among the patients with moderate hypertriglyceridemia, reported as the difference between each olezarsen dose group and the placebo group (the placebo-adjusted change). A total of 1349 patients (254 in the olezarsen 50-mg group, 766 in the olezarsen 80-mg group, and 329 in the placebo group) were included in the primary efficacy analysis. The median age was 64 years, 40% of the patients were women, and the median triglyceride level at baseline was 238.5 mg per deciliter (interquartile range, 190.5 to 307.5). At 6 months, the placebo-adjusted least-squares mean change in triglyceride level was -58.4 percentage points (95% confidence interval [CI], -65.1 to -51.7; P<0.001) in the olezarsen 50-mg group and -60.6 percentage points (95% CI, -67.1 to -54.0; P<0.001) in the olezarsen 80-mg group. The incidence of serious adverse events appeared to be similar across the trial groups. Among patients with moderate hypertriglyceridemia and elevated cardiovascular risk, treatment with olezarsen resulted in significantly greater reduction in triglyceride levels at 6 months than placebo. (Funded by Ionis Pharmaceuticals; ESSENCE-TIMI 73b ClinicalTrials.gov number, NCT05610280.). Show less

Elevated lipoprotein(a) [Lp(a)] is associated with atherosclerotic cardiovascular disease (ASCVD) risk, and vascular inflammation is one mechanism through which Lp(a) causes ASCVD. The authors aimed to evaluate whether interleukin-6 (IL-6), a biomarker associated with inflammation and cardiovascular disease, helps risk-stratify individuals with elevated Lp(a). Data from participants in the MESA (Multi-Ethnic Study of Atherosclerosis) (n = 6,514) and the UK Biobank (UKB) (n = 26,574) were used for this analysis. The associations between Lp(a) and IL-6 with coronary heart disease (CHD) (defined as myocardial infarction or resuscitated cardiac arrest), ASCVD (CHD and ischemic stroke), and peripheral vascular disease (PVD) were evaluated separately and with mutual adjustment in Cox proportional hazard models adjusted for traditional cardiovascular risk factors and high-sensitivity C-reactive protein (hsCRP). HRs were presented per standard deviation. Participants were also grouped by Lp(a) level (≤50 or >50 mg/dL [125 nmol/L]) and IL-6 level (≤ median or > median) in similar models. Participants with higher IL-6 levels were more likely to have higher body mass index, systolic blood pressure, triglycerides, and hsCRP with lower high-density lipoprotein cholesterol. Lp(a) (HR: 1.13; 95% CI: 1.04-1.23 in MESA; HR: 1.11; 95% CI: 1.09-1.13 in UKB) and IL-6 (HR: 1.22; 95% CI: 1.10-1.35 in MESA; HR: 1.19; 95% CI: 1.15-1.24 in UKB) were both independently associated with CHD events when evaluated separately. When evaluated together, no significant change was noted, and interaction testing was not significant. Similar results were seen for ASCVD and PVD. When participants were categorized by both Lp(a) and IL-6 levels, the strongest association for each outcome was noted when both levels were high (for CHD: HR: 1.72; 95% CI: 1.25-2.36 in MESA; HR: 1.39; 95% CI: 1.12-1.72 in UKB). In 2 independent primary prevention cohorts, Lp(a) and IL-6 were independent predictors of ASCVD risk, and their combination identified individuals at highest risk. Show less

Oxidized phospholipids (OxPLs) are carried by apolipoprotein B-100-containing lipoproteins (OxPL-apoB) including lipoprotein(a) (Lp[a]). Both OxPL-apoB and Lp(a) have been associated with calcific aortic valve disease (CAVD). This study aimed to evaluate the associations between OxPL-apoB, Lp(a) and the prevalence, incidence, and progression of CAVD. OxPL-apoB and Lp(a) were evaluated in MESA (Multi-Ethnic Study of Atherosclerosis) and a participant-level meta-analysis of 4 randomized trials of participants with established aortic stenosis (AS). In MESA, the association of OxPL-apoB and Lp(a) with aortic valve calcium (AVC) at baseline and 9.5 years was evaluated using multivariable ordinal regression models. In the meta-analysis, the association between OxPL-apoB and Lp(a) with AS progression (annualized change in peak aortic valve jet velocity) was evaluated using multivariable linear regression models. In MESA, both OxPL-apoB and Lp(a) were associated with prevalent AVC (OR per SD: 1.19 [95% CI: 1.07-1.32] and 1.13 [95% CI: 1.01-1.27], respectively) with a significant interaction between the two (P < 0.01). Both OxPL-apoB and Lp(a) were associated with incident AVC at 9.5 years when evaluated individually (interaction P < 0.01). The OxPL-apoB∗Lp(a) interaction demonstrated higher odds of prevalent and incident AVC for OxPL-apoB with increasing Lp(a) levels. In the meta-analysis, when analyzed separately, both OxPL-apoB and Lp(a) were associated with faster increase in peak aortic valve jet velocity, but when evaluated together, only OxPL-apoB remained significant (ß: 0.07; 95% CI: 0.01-0.12). OxPL-apoB is a predictor of the presence, incidence, and progression of AVC and established AS, particularly in the setting of elevated Lp(a) levels, and may represent a novel therapeutic target for CAVD. Show less

Olezarsen is a GalNAc A randomized, placebo-controlled, double-blind phase 1 study was performed in 28 healthy Japanese American participants treated with olezarsen in single-ascending doses (SAD; 30, 60, 90 mg) or multiple doses (MD; 60 mg every 4 weeks for 4 doses). The primary, secondary, and exploratory objectives were safety and tolerability, pharmacokinetics, and effects of olezarsen on fasting serum triglycerides and apoC-III, respectively. There were 20 participants (16 active:4 placebo) in the SAD part of the study, and 8 participants (6 active:2 placebo) in the MD part of the study. For the primary endpoint, no serious adverse events or clinically relevant laboratory abnormalities were reported. The majority of olezarsen plasma exposure occurred within 24 h post-dose. In the SAD cohorts at Day 15 the percentage reduction in apoC-III/TG was - 39.4%/ - 17.8%, - 60.8%/ - 52.7%, and - 68.1%/ - 39.2% in the 30, 60 and 90 mg doses, respectively, vs 2.3%/44.5% increases in placebo. In the MD cohort, at Day 92 the percentage reduction in apoC-III/TG was - 81.6/ - 73.8% vs - 17.2/ - 40.8% reduction in placebo. Favorable changes were also present in VLDL-C, apoB and HDL-C. Single- and multiple-dose administration of olezarsen was safe, was well tolerated, and significantly reduced apoC-III and triglyceride levels in healthy Japanese Americans. Show less

The roles of lipoprotein(a) [Lp(a)] and related oxidized phospholipids (OxPLs) in the development and progression of coronary disease is known, but their influence on extracoronary vascular disease is not well-established. We sought to evaluate associations between Lp(a), OxPL apolipoprotein B (OxPL-apoB), and apolipoprotein(a) (OxPL-apo(a)) with angiographic extracoronary vascular disease and incident major adverse limb events (MALEs). Four hundred forty-six participants who underwent coronary and/or peripheral angiography were followed up for a median of 3.7 years. Lp(a) and OxPLs were measured before angiography. Elevated Lp(a) was defined as ≥150 nmol/L. Elevated OxPL-apoB and OxPL-apo(a) were defined as greater than or equal to the 75th percentile (OxPL-apoB ≥8.2 nmol/L and OxPL-apo(a) ≥35.8 nmol/L, respectively). Elevated Lp(a) had a stronger association with the presence of extracoronary vascular disease compared to OxPLs and was minimally improved with the addition of OxPLs in multivariable models. Compared to participants with normal Lp(a) and OxPL concentrations, participants with elevated Lp(a) levels were twice as likely to experience a MALE (odds ratio: 2.14, 95% confidence interval: 1.03, 4.44), and the strength of the association as well as the C statistic of 0.82 was largely unchanged with the addition of OxPL-apoB and OxPL-apo(a). Elevated Lp(a) and OxPLs are risk factors for progression and complications of extracoronary vascular disease. However, the addition of OxPLs to Lp(a) does not provide additional information about risk of extracoronary vascular disease. Therefore, Lp(a) alone captures the risk profile of Lp(a), OxPL-apoB, and OxPL-apo(a) in the development and progression of atherosclerotic plaque in peripheral arteries. Show less

Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering. In this phase 2b, randomized, controlled trial, we assigned adults either with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) in a 1:1 ratio to either a 50-mg or 80-mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the percent change in the triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo. Key secondary outcomes were changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. A total of 154 patients underwent randomization at 24 sites in North America. The median age of the patients was 62 years, and the median triglyceride level was 241.5 mg per deciliter. The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons). As compared with placebo, each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, with no significant change in the LDL cholesterol level. The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups. In patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified. (Funded by Ionis Pharmaceuticals; Bridge-TIMI 73a ClinicalTrials.gov number, NCT05355402.). Show less

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. Show less

ApoC-III inhibits lipoprotein lipase and hepatic uptake of triglyceride-rich lipoproteins. It is unknown whether targeting apoC-III affects hepatic steatosis in patients with hypertriglyceridemia. We studied the effect of volanesorsen, a potent antisense oligonucleotide targeting APOC3 mRNA, on hepatic fat fraction (HFF) assessed by MRI in patients with severe hypertriglyceridemia (SHTG, triglycerides ≥500 mg/dL), familial partial lipodystrophy (FPL, triglycerides ≥200 mg/dL) and familial chylomicronemia syndrome (FCS, triglycerides ≥750 mg/dL). The data were evaluated individually in COMPASS (SHTG), APPROACH (FCS), and BROADEN (FPL) trials. The baseline absolute HFF were elevated in all three trials and ranged from 6.3-18.1%. In COMPASS, compared to placebo, volanesorsen significantly reduced the absolute HFF by -3.02% (95% CI, (-5.60, -0.60), p = 0.009) (placebo-adjusted % change from baseline -24.2%, p = 0.034) from baseline to 6 months. In APPROACH a non-significant absolute -1.0% (95% CI, -2.9, 0.0, p = 0.13) reduction in HFF was noted from baseline to 12 months (placebo-adjusted % change from baseline -37.1%, p = 0.20). In BROADEN volanesorsen significantly reduced the absolute HFF by -8.34% (95% CI, -13.01, -3.67, p = 0.001) from baseline to 12 months (placebo-adjusted % change from baseline -52.7%, p = 0.004). In all 3 trials individually, a strong inverse correlation was present between the baseline HFF and the change in HFF in the volanesorsen groups, but not in the placebo groups. In conclusion, apoC-III inhibition with volanesorsen has favorable effects in HFF in patients with different etiologies of hypertriglyceridemia. Show less

Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease. A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200-500 mg/dL (2.26-5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222-329) mg/dL [2.96 (2.51-3.71) mmol/L]. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to <0.0001 compared with placebo). Significant decreases in apoC-III, very low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were also observed. There were no platelet count, liver, or renal function changes in any of the olezarsen groups. The most common adverse event was mild erythema at the injection site. Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease. NCT03385239. Show less

Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and high-density lipoprotein (HDL) remains unexplored. This study sought to interrogate the novel relationship between PCSK9 and HDL in humans. Comparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck (n=656) study revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein-C3, an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 times points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apolipoprotein-C3 from HDL and lower levels of small HDL as measured by nuclear magnetic resonance. Crosslinking mass spectrometry (XLMS) upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin and apolipoprotein-E within the HDL proteome, that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalisation and multimerisation. This study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipaemia as a driver of PCSK9 and apolipoprotein-C3 release from HDL. Show less