Efficacy of Olezarsen in severe hypertriglyceridemia and acute pancreatitis risk: A systematic review and meta-analysis of randomized controlled trials

Efficacy of Olezarsen in severe hypertriglyceridemia and acute pancreatitis risk: A systematic review and meta-analysis of randomized controlled trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Efficacy of Olezarsen in severe hypertriglyceridemia and acute pancreatitis risk: A systematic review and meta-analysis of randomized controlled trials Abdul Rehman, Dhvanit Rajdeep, Jonathan D. Mohnkern, Jacopo Lin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8583537/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Mar, 2026 Read the published version in Digestive Diseases and Sciences → Version 1 posted 9 You are reading this latest preprint version Abstract Purpose Olezarsen has shown efficacy in hypertriglyceridemic and dyslipidemic populations of mixed cohorts, but its effectiveness in severe hypertriglyceridemia(SHTG) is unknown.This is systematic review and meta-analysis to evaluate the efficacy of olezarsen in SHTG and associated risk of pancreatitis. Method PubMed, Embase, and Cochrane databases were systematically searched for published trials comparing olezarsen vs. placebo in SHTG patients up to December 03, 2025. We computed mean difference (MD) and risk ratio (RR) with 95% CI for continuous and binary endpoints, respectively, using a random-effects model.Significance level was set with P-value(< 0.05) Results From 228 database records, three randomized trials involving a total of 1,127 patients were included. Of these, 748 patients (66.3%) received olezarsen. Olezarsen significantly reduced the mean percentage change from baseline of triglyceride (TG) levels (MD = -55.01%;95% CI: -61.97, -48.06; P = .00001), of apolipoprotein C-III levels (MD = -65.66%; 95% CI: -70.75, -60.57; P = .00001) compared to placebo. Significant reductions were also observed for other lipid parameters, specifically Non-high-density lipoprotein cholesterol (non-HDL-C) (MD = -23.92%;95% CI: -26.93, -20.91; P = .00001) and Remnant cholesterol(RC) (MD = -55.30%;95% CI: -62.05, -48.56; P = .00001) with reduced risk of acute pancreatitis (1.2% vs 8.7%; RR = 0.14; 95% CI: 0.07, 0.29; P = .00001) compared to placebo. No significant adverse events were observed between groups. Conclusion Olezarsen significantly reduced TG, apolipoprotein C-III, and other lipid parameters while reducing acute pancreatitis risk without increasing adverse events. These findings are suggestive that olezarsen is an effective alternative therapy for patients with SHTG. Olezarsen Severe hypertriglyceridemia pancreatitis apolipoprotein C-III non-HDL Cholesterol remnant cholesterol Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Hypertriglyceridemia is a common lipid disorder that presents significant clinical challenges, having a strong association with cardiovascular disease, pancreatitis, and metabolic syndrome.[ 1 , 2 ]. Severe hypertriglyceridemia (SHTG), defined as a serum triglyceride (TG) level of 500 mg per deciliter or higher (≥ 5.65 mmol per liter), affects approximately 1 in 100 individuals and is associated with additional clinical consequences, including an increased risk of life-threatening acute pancreatitis.[ 3 , 4 ]. Acute pancreatitis is a highly morbid condition that can result in multi-organ failure, intensive care admission, and prolonged hospitalization, with reported in-hospital mortality up to 8%[ 5 ]. Conventional TG-lowering therapies, such as fibrates and omega-3 fatty acids, often produce only modest reductions in TG levels and have not been shown to reduce the risk of acute pancreatitis[ 6 ]. In addition, these therapies are limited by variable efficacy and tolerability[ 7 ]. Olezarsen is a hepatocyte-targeted, N-acetylgalactosamine-conjugated antisense oligonucleotide that binds apolipoprotein C-III messenger RNA, resulting in reduced apolipoprotein C-III synthesis and enhanced clearance of TG-rich lipoproteins[ 8 ]. While the efficacy of olezarsen in this SHTG remains somewhat controversial, recent pivotal trials have demonstrated promising results[ 8 , 9 ]. However, a comprehensive pooled analysis across clinically meaningful endpoints is still lacking. Prior systematic reviews and meta-analyses have reported the efficacy of olezarsen in hypertriglyceridemic or dyslipidemic cohorts; however, these studies were limited by small sample sizes, underpowered individual endpoints, lack of restriction to SHTG, and the absence of systematic evaluation of pancreatitis as a clinical outcome[ 10 – 13 ]. Therefore, we aimed to perform a comprehensive systematic review and meta-analysis to evaluate the efficacy and safety of olezarsen specifically in the SHTG population. Methods This systematic review with meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under protocol number CRD420251243520. The study was conducted in accordance with the Cochrane Collaboration Handbook for Systematic Review of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines[ 14 , 15 ]. Eligibility criteria We included studies that met the following eligibility criteria: (1) peer-reviewed randomized controlled trials (RCTs); (2) comparing olezarsen with placebo; (3) adults aged > 18 years with SHTG at high risk for pancreatitis, as defined by trial-specific TG thresholds; and (4) reporting at least one clinical outcome of interest. We excluded studies with (1) observational studies (cohort, case-control, or cross-sectional), case reports, case series, conference abstracts without complete data, narrative reviews, or non-randomized trials; (2) did not report outcomes of interest; and (3) included overlapping patient populations with larger trials. No restrictions were placed on publication date or language. Search strategy and data extraction A systematic search was performed in PubMed, Embase, and Cochrane Central Register of Controlled Trials from database inception to December 3, 2025. The search strategy included the following terms: (Olezarsen OR ISIS 678354 OR "AKCEA-APOCIII-LRx") AND ("hypertriglyceridemia"[MeSH] OR hypertriglyceridemia OR chylomicronemia OR "familial chylomicronemia syndrome" OR FCS), with database-specific modifications applied as appropriate. Reference lists of all included studies and of relevant systematic reviews and meta-analyses were manually screened to identify additional eligible studies. Two authors (A.R. and D.R.) independently extracted the data using standardized spreadsheets, with discrepancies resolved by consensus. Extracted data included (1) the number and baseline characteristics of participants in the intervention and control groups; (2) treatment differences in mean percentage change from baseline for continuous outcomes; (3) the number of events in the olezarsen and placebo groups for binary outcomes; and (4) baseline definitions of TG of each included trial as shown in Supplementary Table S1 . Endpoints and subgroup analysis Primary outcomes included: (1) mean % change from baseline in TG levels; (2) mean % change from baseline in apolipoprotein C-III levels; and (3) pancreatitis risk. Secondary outcomes included: (1) Non-high-density lipoprotein cholesterol (non-HDL-C); (2) high-density lipoprotein cholesterol(HDL-C); (3) low-density lipoprotein cholesterol(LDL-C); and (4) safety outcomes, including serious adverse events, any adverse events, and hepatic enzyme elevations (alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ≥ 3x the upper limit of normal). Subgroup analyses were performed to investigate dose-dependent effects on the mean % change from baseline in TG levels and in apolipoprotein C-III levels. Quality assessment The Cochrane tool for assessing risk of bias in randomized trials (RoB 2) was utilized for quality assessment of randomized studies. The risk of bias evaluation was performed independently by two authors (A.R., D.R.), with disagreements resolved by consensus. Publication bias was evaluated using funnel plots for the mean percentage change from baseline in triglyceride and apolipoprotein C-III levels to assess symmetry across studies with comparable weights. Sensitivity analyses We performed (1) leave-one-out sensitivity analyses for primary outcomes to assess the effects of individual studies on the pooled analysis; (2) given the genetic distinction between familial chylomicronemia syndrome (FCS) and non-FCS populations, prespecified sensitive analyses were performed across outcomes by excluding the FCS population to assess the robustness of pooled results. Statistical Analysis Treatment effects for continuous endpoints were pooled using mean difference (MD) with 95% confidence intervals (CIs) using the generic inverse method. In comparison, binary outcomes were analyzed using risk ratios (RR) with 95% CIs. Heterogeneity was examined with Cochran’s Q test, I² statistics, and Tau-square (τ²) using the restricted maximum-likelihood estimator. Heterogeneity was reported as low (I² = 0–25%), moderate (I² = 26–50%), or high (I² > 50%). Confidence intervals (CI) for summary effects were calculated using Hartung–Knapp–Sidik–Jonkman (HKSJ) when appropriate; otherwise, Wald or classic type depending upon the τ² values, in accordance with Cochrane’s recommendation[ 16 ]. A random-effects model was used for all analyses, irrespective of heterogeneity magnitude, due to anticipated clinical and methodological variability among studies. Statistical analyses were performed using RevMan web 9.17.0. Statistical significance was defined as a P value < 0.05[ 17 ]. Results Study selection and characteristics Our systematic search identified 228 records, as shown in Fig. 1 . After removal of duplicates and exclusion based on title and abstract screening, 20 full-text articles were assessed for eligibility. Ultimately, three RCTs (BALANCE,[ 8 ]CORE-TIMI 72a,[ 9 ] CORE-TIMI 72b[ 9 ]) were included in the meta-analysis, comprising a total of 1,127 patients, of whom 748 were assigned to the olezarsen group. The mean or median age ranged from 43.2 years to 55 years. Females accounted for 26% of the study population, and the follow-up duration was 12 months. Study characteristics are summarized in Table 1 , with additional details on baseline lipid profiles provided in Table 2 . Table 1 Baseline characteristics of included trials Author, Year Population I/C N Age* (yr) Female n (%) BMI (kg/m²) DM n (%) ASCVD n (%) Pancr.Hx n (%) Statins n (%) Fibrates n (%) Omega-3 n (%) Follow-up months Stroes et al., 2024 8 FCS Olez(80mg) 22 47.7 ± 13.3 11(50) 25.1 ± 6.0 7 (32) - 17 (77.3) 5 (22) 11 (50.0) 12 (55) 12 Olez(50mg) 21 43.2 ± 12.1 15(71) 22.4 ± 3.5 3 (14) - 15 (71.4) 4 (19.0) 8(38) 6 (29) Placebo 23 44.0 ± 14.7 12(52) 24.2 ± 4.1 6 (26) - 15 (65.2) 7 (30) 11 (48) 7 (30) Marston et al., 2025 9 SHTG (CORE-TIMI 72a) Olez(80m) 204 54 (45–61) 53 (26.0) 31.2 (28.1–34.7) 127 (62.3) 50 (24.5) 43 (21.1) 153(75) 130(63.7) 70(34.3) 12 Olez(50mg) 205 54 (45–61) 52 (25.4) 31.2 (28.4–35.2) 128 (62.4) 37 (18.0) 51 (24.9) 144(70.2) 133(64.9) 68(33.2) Placebo 208 54 (45–62) 42 (20.2) 30.9 (28.2–34.6) 113 (54.3) 54 (26.0) 48 (23.1) 147(70.7) 146(70.2) 70(33.7) Marston et al., 2025 9 SHTG (CORE-TIMI 72b) Olez (80 mg) 147 55 (48–62) 37 (25.2) 30.7 (27.7–33.5) 101 (68.7) 45 (30.6) 20 (13.6) 115 (78.2) 88 (59.9) 38 (25.9) 12 Olez (50 mg) 149 55 (48–62) 39 (26.2) 30.9 (27.9–34.8) 102 (68.5) 41 (27.5) 17 (11.4) 111 (74.5) 87 (58.4) 46 (30.9) Placebo 148 54 (44–62) 27 (18.2) 32.2 (28.3–36.1) 102 (68.9) 45 (30.4) 21 (14.2) 114(77) 90 (60.8 48 (32.2) ASCVD: Atherosclerotic cardiovascular disease; BMI: Body mass index; DM: Diabetes mellitus; FCS: Familial chylomicronemia syndrome; I/C: intervention/Control; N: Number of subjects; Olez: Olezarsen; Omega3: Omega3 fatty acids; Pancr. Hx : Pancreatitis history; SHTG : Severe hypertriglyceridemia; Kg/m²: Kilograms per square meter (Units for BMI); n(%): Number and percentage of subjects; yr: year *± values represent mean and SD; otherwise, data in the table represent median and interquartile range or number (percentage) Table 2 Baseline lipid profile of included trials Author, Year Population I/C N Triglyceride (mg/dL)* Apolipoprotein C-III (mg/dL) Non-HDL Cholesterol (mg/dL) LDL Cholesterol (mg/dL) Apolipoprotein B (mg/dL) HDL Cholesterol (mg/dL) Remnant Cholesterol (mg/dL) Stroes et al., 2024 8 FCS Olez (80 mg) 22 2613 ± 1499 27.5 ± 11.6 262.9 ± 100.4 22.8 ± 14.1 58.4 ± 17.2 14.5 ± 4.5 245.7 ± 110.9 Olez (50 mg) 21 2684 ± 1235 27.7 ± 10.5 307.6 ± 101.8 17.6 ± 8.5 65.2 ± 13.5 15.7 ± 4.0 293.2 ± 103.1 Placebo 23 2596 ± 1256 27.7 ± 11.7 271.3 ± 113.3 16.7 ± 8.4 59.7 ± 18.9 14.7 ± 3.8 255.3 ± 114.4 Marston et al., 2025 9 SHTG (CORE-TIMI 72a) Olez (80 mg) 204 810.0 (579.8–1396.0) 33.8 (25.5–45.3) 203.2 (160.8–258.4) 57.5 (37.2–84.8) 101.8 (81.0–122.2) 25.6 ± 8.1 130.4 (82.2–180.1) Olez (50 mg) 205 845.5 (630.0–1427.0) 34.6 (28.4–50.9) 197.5 (160.5–252.0) 59.0 (41.8–83.3) 105.0 (88.2–125.0) 25.6 ± 8.2 137.6 (97.3–197.3) Placebo 208 838.2 (606.2–1233.0) 34.1 (26.1–43.0) 199.2 (161.0–242.0) 58.5 (41.0–80.5) 101.6 (87.1–121.8) 26.1 ± 12.1 130.4 (92.7–187.5) Marston et al., 2025 9 SHTG (CORE-TIMI 72b Olez(80 mg) 147 750.5 (572.0–1145.5) 34.1 (26.0–43.9) 186.0 (149.5–241.0) 60.0 (40.5–81.0) 101.5 (85.8–120.3) 27.7 ± 8.9 125.0 (79.5–199.2) Olez(50 mg) 149 762.0 (600.5–1114.5) 34.9 (28.0–44.1) 197.5 (159.0–240.0) 66.6 (44.8–90.0) 109.2 (93.9–129.5) 28.7 ± 8.6 127.9 (87.0–164.0) Placebo 148 729.8 (577.0–1097.2) 34.8 (27.1–44.0) 181.0 (147.0–217.0) 57.8 (39.2–81.5) 103.5 (81.7–118.8) 26.7 ± 9.3 109.6 (76.8–165.8) FCS : Familial chylomicronemia syndrome; HDL Cholesterol: High-density lipoprotein cholesterol; I/C: Intervention/Control; LDL Cholesterol: Low-density lipoprotein cholesterol; N: Number of subjects; Non-HDL Cholesterol: Non-high density lipoprotein cholesterol; Olez: Olezarsen; SHTG: Severe hypertriglyceridemia *± values represent mean and SD; otherwise, data in the table represent median and interquartile range. TG and apolipoprotein C-III at 6 and 12 months Olezarsen demonstrated a significant reduction in the mean percentage change from baseline in TG levels at 6 months (MD = -54.41%; 95% CI: -70.85, -37.97; P = .0004; I 2 = 81%) and at 12 months (MD = -54.37%; 95% CI: -61.19, -47.55; P = .00001; I 2 = 21%), with an overall mean percentage change of -55.01% (95% CI: -61.97, -48.06; P = .00001; I 2 = 62%; Fig. 2 ) compared with placebo. Similarly, olezarsen was associated with a significant reduction in the mean percentage change from baseline in apolipoprotein C-III levels at 6 months (MD = -67.16%; 95% CI: -75.39, -58.94; P = .00001; I 2 = 76%) and at 12 months (MD = -64.03%; 95% CI: -73.11, -54.95; P = .00001; I 2 = 74%), with an overall mean percentage change of -65.66% (95% CI: -70.75, -60.57; P = .00001; I 2 = 74%; Fig. 3 ). Given the substantial heterogeneity observed across outcomes, leave-one-out sensitivity analyses were performed to assess the robustness of the pooled estimates and to explore potential sources of heterogeneity. These analyses identified the CORE-TIMI 72a trial 9 as the primary contributor to heterogeneity. After exclusion of this study, heterogeneity was significantly reduced for the mean percentage change in TG levels at 6 months (MD = -46.99%; 95% CI: -66.09, -27.89; P = .004; I 2 = 48%) and at 12 months (MD = -46.3%; 95% CI: -55.32, -42.53; P = .0002; I 2 = 0%), with an overall mean percentage change of -49.12% (95% CI: -54.87, -43.38; P = .00001; I 2 = %). Similar reductions in heterogeneity were observed for apolipoprotein C-III levels at 6 months (MD = -54.1%; 95% CI: -70.96, -52.46; P = .0002; I 2 = 23%) and at 12 months (MD = -57.65%; 95% CI: -69.04, -46.25; P = .0005; I 2 = 14%), with and overall mean percentage change of -59.83% (95% CI: -65.14, -54.52; P = .00001; I 2 = 20%). These findings are presented in Supplementary Figure S1 and Figure S2. Sensitivity analyses excluding patients with familial chylomicronemia syndrome demonstrated that statistically significant reductions in the mean percentage change from baseline in TG and apolipoprotein C-III levels persisted, although substantial heterogeneity remained (Supplementary Figure S3 and Figure S4). Subgroup analyses evaluating dose-dependent effects showed significant reductions in TG levels at both the 50-mg dose (MD = -50.81; 95% CI: -63.28, -38.34; P = .0001; I² = 64%) and the 80-mg dose (MD = -59.33%; 95% CI: -68.89, -49.77; P = .0001; I² = 57%), with no significant subgroup difference (P = 0.16; Fig. 4 ). a In subgroup analysis, each row of the study represents a dose strength of 50 mg, first at 6 months and then at 12 months; similarly, this is the case with the 80 mg dose strength Similarly, apolipoprotein C-III levels were significantly reduced at both the 50-mg dose (MD = -63.11%; 95% CI: -71.22, -55.01; P = .00001; I² = 69%) and the 80-mg dose (MD = -69.34%; 95% CI: -77.76, -60.92; P = .00001; I² = 74%), with no significant subgroup difference (p = 0.17; Fig. 5 ). a In subgroup analysis, each row of the study represents a dose strength of 50 mg (a) first at 6 months and then (b) at 12 months; similarly, this is the case with the 80 mg dose strength. Acute pancreatitis Olezarsen was associated with a significant reduction in the incidence of acute pancreatitis compared with placebo (1.2% vs 8.7%; RR = 0.14; 95% CI: 0.07, 0.29; P = .00001; I² = 0%; Fig. 6 ), corresponding to an 86% relative risk reduction. Trial sequential analysis is shown in Supplementary Figure S5. Other lipid parameters Olezarsen was associated with a significant reduction in the mean percentage change from baseline in Non-high-density lipoprotein cholesterol (non-HDL-C) at 6 months (MD = -24.35%; 95% CI: -30.04, -18.66; P = .0001; I 2 = 61%) and at 12 months (MD = -22.90%; 95% CI: -26.47, -19.32; P = .0001; I 2 = 0%), with an overall mean percentage change of -23.92% (95% CI: -26.93, -20.91; P = .00001; I 2 = 40%; Supplementary Figure S6). A significant reduction in Remnant Cholesterol(RC) was also observed at 6 months (MD = -58.27%; 95% CI: -72.60, -43.95; P = .001; I 2 = 71%) and at 12 months (MD = -52.20%; 95% CI: -61.43, -42.98; P = .0004; I 2 = 0%), with an overall mean percentage change of -55.30% ( 95% CI: -62.05, -48.56; P = .00001; I 2 = 59%; Supplementary Figure S7). Mean percentage change in High density lipoprotein cholesterol(HDL-C) increased significantly at 6 months (MD = 69.42%; 95% CI: 50.90, 87.94; P = .001; I 2 = 82%) and at 12 months (MD = 67.78%; 95% CI: 52.08, 83.48; P = .0008; I 2 = 73%), with an overall mean percentage change of 68.60% ( 95% CI: 60.22, 76.99; P = .00001; I 2 = 75%; Supplementary Figure S8). LDL Cholesterol(LDL-C) increased significantly in the olezarsen group at 6 months (MD = 52.75%; 95% CI: 42.17, 63.33; P = .00001; I 2 = 31%) and at 12 months (MD = 46.1%; 95% CI: 43.74, 62.57; P = .00001; I 2 = 0%), with an overall mean percentage change of 53.25% (95% CI: 46.85, 59.64; P = .00001; I² = 0%; Supplementary Figure S9). Safety parameters The olezarsen group experienced a lower incidence of serious adverse events compared with placebo (RR = 0.63; 95% CI: 0.41, 0.98; P = .04; I² = 24%; Supplementary Figure S10A). There was no significant difference between groups in the incidence of any adverse events (RR = 0.97; 95% CI: 0.88, 1.07; P = .55; I 2 = 41%; Supplementary Figure S10B)or in hepatic enzyme elevation, including AST ≥ 3x the upper limit of normal (RR = 2.04; 95% CI: 0.83, 4.98; P = .12; I 2 = 6%; Supplementary Figure S10C) and ALT ≥ 3x the upper limit of normal (RR = 0.72; 95% CI: 0.04, 13.72; P = .83; I 2 = 74%; Supplementary Figure S10D). GRADE assessment GRADE assessment for primary and clinically relevant outcomes was also done, which showed moderate tohigh certainty of evidence across outcomes, as shown in Supplementary Table S2. Risk of bias assessment The Risk of Bias 2 (RoB 2) tool was used to assess quality. No studies were considered to be at high risk of bias, as described in Supplementary Figure S11. In the funnel plot analysis, studies were distributed symmetrically by weight and converged toward the pooled effect as weight increased (Supplementary Figure S12 and Figure S13). Egger’s test was not performed because fewer than 10 studies were included (k < 10). Discussion We conducted a systematic review and meta-analysis comprising 1,127 patients with SHTG. The main findings associated with olezarsen were significant reductions in: (1) the mean percentage change from baseline in TG levels at both 6 and 12 months, compared with placebo; (2) the mean percentage change from baseline in apolipoprotein C-III levels at both 6 and 12 months, compared with placebo; and (3) other lipid parameters, including non-HDL cholesterol and remnant cholesterol. Additionally, no significant difference in adverse events was observed between the treatment groups. Olezarsen is an antisense oligonucleotide that targets messenger RNA (mRNA) encoding apolipoprotein C-III, thereby reducing apolipoprotein C-III production and lowering plasma triglyceride levels.[ 18 , 19 ]. TGs themselves are not inherently toxic to the pancreas; instead, pancreatic injury occurs when TGs are hydrolyzed by pancreatic lipase into free fatty acids (FFAs), leading to lipotoxicity[ 20 ]. Excess FFAs aggregate into detergent-like micelles that induce ischemia, promote acidosis, activate trypsinogen into trypsin, and ultimately result in pancreatic autodigestion.[ 21 ]. Previous systematic reviews and meta-analyses have consistently shown reductions in TG and apolipoprotein C-III levels among hypertriglyceridemic patients[ 10 – 13 , 22 ]. In one such review, the mean percentage reduction in TG levels was − 44.64%, and the reduction in apolipoprotein C-III was − 65.38%[ 22 ]. Our meta-analysis demonstrated a greater reduction in TGs (-55.01%) and a comparable reduction in apolipoprotein C-III (-65.66%). While consistent with prior findings, earlier reviews were limited by smaller sample sizes, underpowered clinical endpoints, inclusion of mixed patient populations, and the absence of pancreatitis as a systematically evaluated outcome. In contrast, our analysis included larger trials restricted to patients with SHTG, demonstrated low risk of bias, and evaluated pancreatitis as a clinically meaningful endpoint, showing a substantial relative risk reduction supported by trial sequential analysis. We observed a relative increase in LDL cholesterol of approximately 53%, which warrants mechanistic interpretation rather than immediate clinical concern[ 9 ]. When TG concentrations are markedly reduced, accelerated lipolysis of TG-rich very-low-density lipoproteins (VLDL) and chylomicrons leads to the generation of LDL particles that carry liberated cholesteryl esters[ 23 ]. Importantly, this shift was accompanied by reductions in non-HDL cholesterol (-23.26%) and remnant cholesterol (-55.30%), lipid parameters that more accurately reflect atherogenic burden than LDL cholesterol alone in patients with SHTG[ 9 ]. The net transition from a chylomicron-dominant to an LDL-dominant lipoprotein profile is thought to improve cardiovascular risk, as remnant particles are inherently more inflammatory and prothrombotic than LDL particles[ 23 ]. Recent advances in human genetics further support targeting apolipoprotein C-III mRNA to reduce TG levels and cardiovascular risk. Individuals with loss-of-function variants in the APOC3 gene exhibit a lower risk of subclinical and overt atherosclerosis.[ 24 ]. Conventional TG-lowering therapies, including pemafibrate, fenofibrate, niacin, and omega-3 fatty acids, have demonstrated efficacy in reducing TG levels but have failed to show consistent improvements in cardiovascular outcomes or safety signals[ 25 – 28 ].In patients with SHTG, particularly those with FCS, the primary therapeutic goal is to reduce TG levels to prevent recurrent episodes of acute pancreatitis[ 22 ]. Fibrates and omega-3 fatty acids have not demonstrated efficacy in reducing pancreatitis risk in this population[ 6 ]. Our findings suggest that olezarsen provides a meaningful reduction in pancreatitis risk, offering a novel therapeutic option that may transform a recurrent, life-threatening condition into a manageable metabolic disorder. The study design and enrolment criteria varied among the included trials. For example, the BALANCE trial enrolled patients with genetically confirmed FCS[ 8 ], whereas the CORE-TIMI trials included patients with multifactorial SHTG[ 9 ]. However, both populations share a common downstream pathophysiology characterized by impaired clearance of TG-rich lipoproteins mediated through the apolipoprotein C-III pathway. Because olezarsen directly targets this shared mechanism, pooling data across trials was considered clinically meaningful for lipid-lowering and pancreatitis-related outcomes. Anticipated heterogeneity was addressed using a random-effects model and prespecified sensitivity analyses stratified by FCS status. Prior trials evaluating plozasiran for hypertriglyceridemia reported mild to moderate elevations in liver transaminases[ 29 ]. In contrast, our analysis did not identify significant liver-related adverse effects associated with olezarsen, suggesting a more favorable safety and tolerability profile. Olezarsen also appears to provide improved safety compared to Volesarsen, another apolipoprotein C-III mRNA inhibitor. While Volanesorsen is effective in treating hypertriglyceridemia, its use is limited by safety concerns, particularly thrombocytopenia, which requires regular platelet monitoring[ 30 ]. Olezarsen appears to mitigate these risks while maintaining effective TG reduction [ 31 – 33 ]Differences in molecular structure, binding specificity, and pharmacokinetics may explain its improved safety profile. Nonetheless, continued long-term monitoring remains essential to ensure sustained safety. Limitations Our systematic review and meta-analysis has specific limitations that merit consideration. First, the analysis included only three RCTs, which limits the statistical power for rare safety events despite the robust efficacy signal. Second, the duration of follow-up in the included studies ranged from 6 to 12 months; long-term outcomes of lipid endpoints, pancreatitis, and cardiovascular mortality remained underexplored. Third, we observed substantial statistical heterogeneity in most outcomes, driven by differences in baseline characteristics and study design between the FCS and broader hypertriglyceridemia populations. Nevertheless, we performed a prespecified sensitivity analysis, and the results remained consistent across outcomes. Fourth, we have assessed the efficacy of olezarsen across both populations, but future trials are still needed to determine population-specific outcomes. Finally, while the increase in LDL cholesterol is mechanistically understood, the net effect of this change on long-term atherosclerotic plaque burden in this specific population remains to be empirically quantified in multi-year outcome trials. Conclusion This systematic review and meta-analysis of olezarsen in patients with SHTG demonstrated significant reductions in TG, apolipoprotein C-III, and other lipid parameters, including non-HDL and remnant cholesterol. Olezarsen was also associated with a reduced risk of acute pancreatitis, without an increase in adverse events. These findings support olezarsen as an effective therapeutic option for patients with SHTG. Abbreviations ALT Alanine aminotransferase APOC3 Apolipoprotein C-III gene AST Aspartate aminotransferase ASCVD Atherosclerotic cardiovascular disease BMI Body mass index CI Confidence interval DM Diabetes mellitus FCS Familial chylomicronemia syndrome FFA Free fatty acid GRADE Grading of Recommendations Assessment, Development and Evaluation HDL High-density lipoprotein HKSJ Hartung–Knapp–Sidik–Jonkman method LDL Low-density lipoprotein Non-HDL Non–high–density lipoprotein REML Restricted maximum likelihood RR Risk ratio RoB 2 Risk of Bias version 2 tool SHTG Severe hypertriglyceridemia TG Triglyceride ULN Upper limit of normal VLDL Very-low-density lipoprotein Declarations Funding No funding and grant received to conduct this study. Data Availability Data are available from the corresponding author upon reasonable request. Conflict of interest The authors declare no conflict of interest. Ethical statement This study is a systematic review and meta-analysis of previously published studies. No new human or animal subjects were involved, and therefore institutional review board approval and informed consent were not required. Publication ethics statement The authors affirm adherence to the guidelines of the committee on publication ethics (COPE) and the recommendations of the international committee of medical journal editors (ICMJE), defining the role of authors and contributors Author contributions Conceptualization: A.R.; Data curation: A.R., D.R.; Formal analysis: A.R., J.D.M.; Writing—original draft: A.R., J.D.M., J.L., D.R.; Writing—review and editing: A.R., J.D.M., J.L., D.R. All authors have approved the final article for submission. References Merkel M, Müller-Wieland D, Laufs U, Parhofer KG. Triglyzeride – Aktuelle Bewertung als Risikomarker und Therapieziele. 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Supplementary Files Supplementaryappendix.docx Cite Share Download PDF Status: Published Journal Publication published 21 Mar, 2026 Read the published version in Digestive Diseases and Sciences → Version 1 posted Editorial decision: Revision requested 11 Feb, 2026 Reviews received at journal 02 Feb, 2026 Reviews received at journal 27 Jan, 2026 Reviewers agreed at journal 17 Jan, 2026 Reviewers agreed at journal 14 Jan, 2026 Reviewers invited by journal 14 Jan, 2026 Editor assigned by journal 13 Jan, 2026 Submission checks completed at journal 13 Jan, 2026 First submitted to journal 12 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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07:57:26","extension":"png","order_by":30,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4917,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/d6e3f8dde6dc56257b9a6ffa.png"},{"id":100136599,"identity":"1b64925a-6ea2-42fb-a1f6-f0c16a2a794c","added_by":"auto","created_at":"2026-01-13 10:45:55","extension":"png","order_by":31,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":935,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/d82d927b07b4708a059df1a6.png"},{"id":100368061,"identity":"acde093b-9f6c-4545-a600-c3d2c4a335e3","added_by":"auto","created_at":"2026-01-16 07:57:33","extension":"png","order_by":32,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":65564,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/25ee03c8ca97e3341218ec8d.png"},{"id":100366570,"identity":"2f1d26e9-4401-4d7c-a4ba-d0cb113c1798","added_by":"auto","created_at":"2026-01-16 07:56:22","extension":"png","order_by":33,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":64743,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/892e1b790b6b31f41b204ec3.png"},{"id":100136601,"identity":"94fadb47-e5e4-4761-b3f4-f864297f842d","added_by":"auto","created_at":"2026-01-13 10:45:55","extension":"xml","order_by":34,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":114172,"visible":true,"origin":"","legend":"","description":"","filename":"c4af892fd1b545fc9e814a40da650fca1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/93c64c7c636973a1826a95bd.xml"},{"id":100136608,"identity":"68f50bcd-9cd1-4cd7-8dd0-07f226c1b6bd","added_by":"auto","created_at":"2026-01-13 10:45:56","extension":"html","order_by":35,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":128344,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/93552cb457695f5ef0e1d0c9.html"},{"id":100136571,"identity":"645d55fe-c4ba-469e-8d17-454e1c33ba86","added_by":"auto","created_at":"2026-01-13 10:45:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":228774,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram of study screening and selection.The search of PubMed, Cochrane, and Embase identified 228 records, of which 30 full-text articles were assessed for eligibility. Ultimately, three randomized controlled trials were included in the final analysis.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/f1a5643b65daffdad13205c0.png"},{"id":100136574,"identity":"a99fc1d5-09fe-428a-96ce-6b22396f7c52","added_by":"auto","created_at":"2026-01-13 10:45:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":862584,"visible":true,"origin":"","legend":"\u003cp\u003eSignificant difference in the mean % change in TG levels from baseline.(a) at 6 months (b) at 12 months\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/604516c41bff36da807e7739.png"},{"id":100367872,"identity":"7b8ffb59-5a24-42f3-a944-2db759189eea","added_by":"auto","created_at":"2026-01-16 07:57:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1026619,"visible":true,"origin":"","legend":"\u003cp\u003eSignificant difference in the mean % change from baseline in apolipoprotein C-III levels.(a) at 6 months (b) at 12 months\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/0203176df03727dc85ac6846.png"},{"id":100366820,"identity":"8033eb45-5fcf-4961-abe4-7d562fdcb656","added_by":"auto","created_at":"2026-01-16 07:56:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1061958,"visible":true,"origin":"","legend":"\u003cp\u003eMean % change of triglycerides at different dose strengths\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea \u003c/sup\u003eIn subgroup analysis, each row of the study represents a dose strength of 50 mg, first at 6 months and then at 12 months; similarly, this is the case with the 80 mg dose strength\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/2447fa0584b75b79c4750850.png"},{"id":100366576,"identity":"690e7f2b-208b-4b64-99fe-7db8ba7f997d","added_by":"auto","created_at":"2026-01-16 07:56:22","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1025246,"visible":true,"origin":"","legend":"\u003cp\u003eMean % change of apolipoprotein C-III at different dose strengths\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eIn subgroup analysis, each row of the study represents a dose strength of 50 mg (a) first at 6 months and then (b) at 12 months; similarly, this is the case with the 80 mg dose strength.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/1c642a8426b80537b2c34fb4.png"},{"id":100367873,"identity":"4a1745b0-66a4-440e-84d2-3b1eaa76240b","added_by":"auto","created_at":"2026-01-16 07:57:24","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":317658,"visible":true,"origin":"","legend":"\u003cp\u003eReduced risk of pancreatitis in the Olezarsen group.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/5ac33a95f8b347a611d945f1.png"},{"id":105223359,"identity":"9debbdd8-7749-4a33-98fd-4f04a1200a9e","added_by":"auto","created_at":"2026-03-23 16:05:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5029683,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/ce5ca153-6d5b-4781-b3bf-607ec80ca9cc.pdf"},{"id":100136573,"identity":"91a49640-4990-4612-90a1-0d4c4b6d537b","added_by":"auto","created_at":"2026-01-13 10:45:55","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":1315056,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryappendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-8583537/v1/7ed039984be0695972a370bd.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of Olezarsen in severe hypertriglyceridemia and acute pancreatitis risk: A systematic review and meta-analysis of randomized controlled trials","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHypertriglyceridemia is a common lipid disorder that presents significant clinical challenges, having a strong association with cardiovascular disease, pancreatitis, and metabolic syndrome.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Severe hypertriglyceridemia (SHTG), defined as a serum triglyceride (TG) level of 500 mg per deciliter or higher (\u0026ge;\u0026thinsp;5.65 mmol per liter), affects approximately 1 in 100 individuals and is associated with additional clinical consequences, including an increased risk of life-threatening acute pancreatitis.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Acute pancreatitis is a highly morbid condition that can result in multi-organ failure, intensive care admission, and prolonged hospitalization, with reported in-hospital mortality up to 8%[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Conventional TG-lowering therapies, such as fibrates and omega-3 fatty acids, often produce only modest reductions in TG levels and have not been shown to reduce the risk of acute pancreatitis[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In addition, these therapies are limited by variable efficacy and tolerability[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOlezarsen is a hepatocyte-targeted, N-acetylgalactosamine-conjugated antisense oligonucleotide that binds apolipoprotein C-III messenger RNA, resulting in reduced apolipoprotein C-III synthesis and enhanced clearance of TG-rich lipoproteins[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. While the efficacy of olezarsen in this SHTG remains somewhat controversial, recent pivotal trials have demonstrated promising results[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, a comprehensive pooled analysis across clinically meaningful endpoints is still lacking.\u003c/p\u003e \u003cp\u003ePrior systematic reviews and meta-analyses have reported the efficacy of olezarsen in hypertriglyceridemic or dyslipidemic cohorts; however, these studies were limited by small sample sizes, underpowered individual endpoints, lack of restriction to SHTG, and the absence of systematic evaluation of pancreatitis as a clinical outcome[\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Therefore, we aimed to perform a comprehensive systematic review and meta-analysis to evaluate the efficacy and safety of olezarsen specifically in the SHTG population.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e This systematic review with meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under protocol number CRD420251243520. The study was conducted in accordance with the Cochrane Collaboration Handbook for Systematic Review of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria\u003c/h2\u003e \u003cp\u003eWe included studies that met the following eligibility criteria: (1) peer-reviewed randomized controlled trials (RCTs); (2) comparing olezarsen with placebo; (3) adults aged\u0026thinsp;\u0026gt;\u0026thinsp;18 years with SHTG at high risk for pancreatitis, as defined by trial-specific TG thresholds; and (4) reporting at least one clinical outcome of interest. We excluded studies with (1) observational studies (cohort, case-control, or cross-sectional), case reports, case series, conference abstracts without complete data, narrative reviews, or non-randomized trials; (2) did not report outcomes of interest; and (3) included overlapping patient populations with larger trials. No restrictions were placed on publication date or language.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSearch strategy and data extraction\u003c/h3\u003e\n\u003cp\u003eA systematic search was performed in PubMed, Embase, and Cochrane Central Register of Controlled Trials from database inception to December 3, 2025. The search strategy included the following terms: (Olezarsen OR ISIS 678354 OR \"AKCEA-APOCIII-LRx\") AND (\"hypertriglyceridemia\"[MeSH] OR hypertriglyceridemia OR chylomicronemia OR \"familial chylomicronemia syndrome\" OR FCS), with database-specific modifications applied as appropriate.\u003c/p\u003e \u003cp\u003eReference lists of all included studies and of relevant systematic reviews and meta-analyses were manually screened to identify additional eligible studies. Two authors (A.R. and D.R.) independently extracted the data using standardized spreadsheets, with discrepancies resolved by consensus. Extracted data included (1) the number and baseline characteristics of participants in the intervention and control groups; (2) treatment differences in mean percentage change from baseline for continuous outcomes; (3) the number of events in the olezarsen and placebo groups for binary outcomes; and (4) baseline definitions of TG of each included trial as shown in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e.\u003c/p\u003e\n\u003ch3\u003eEndpoints and subgroup analysis\u003c/h3\u003e\n\u003cp\u003ePrimary outcomes included: (1) mean % change from baseline in TG levels; (2) mean % change from baseline in apolipoprotein C-III levels; and (3) pancreatitis risk. Secondary outcomes included: (1) Non-high-density lipoprotein cholesterol (non-HDL-C); (2) high-density lipoprotein cholesterol(HDL-C); (3) low-density lipoprotein cholesterol(LDL-C); and (4) safety outcomes, including serious adverse events, any adverse events, and hepatic enzyme elevations (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]\u0026thinsp;\u0026ge;\u0026thinsp;3x the upper limit of normal).\u003c/p\u003e \u003cp\u003eSubgroup analyses were performed to investigate dose-dependent effects on the mean % change from baseline in TG levels and in apolipoprotein C-III levels.\u003c/p\u003e\n\u003ch3\u003eQuality assessment\u003c/h3\u003e\n\u003cp\u003eThe Cochrane tool for assessing risk of bias in randomized trials (RoB 2) was utilized for quality assessment of randomized studies. The risk of bias evaluation was performed independently by two authors (A.R., D.R.), with disagreements resolved by consensus. Publication bias was evaluated using funnel plots for the mean percentage change from baseline in triglyceride and apolipoprotein C-III levels to assess symmetry across studies with comparable weights.\u003c/p\u003e\n\u003ch3\u003eSensitivity analyses\u003c/h3\u003e\n\u003cp\u003eWe performed (1) leave-one-out sensitivity analyses for primary outcomes to assess the effects of individual studies on the pooled analysis; (2) given the genetic distinction between familial chylomicronemia syndrome (FCS) and non-FCS populations, prespecified sensitive analyses were performed across outcomes by excluding the FCS population to assess the robustness of pooled results.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eTreatment effects for continuous endpoints were pooled using mean difference (MD) with 95% confidence intervals (CIs) using the generic inverse method. In comparison, binary outcomes were analyzed using risk ratios (RR) with 95% CIs. Heterogeneity was examined with Cochran\u0026rsquo;s Q test, I\u0026sup2; statistics, and Tau-square (τ\u0026sup2;) using the restricted maximum-likelihood estimator. Heterogeneity was reported as low (I\u0026sup2; = 0\u0026ndash;25%), moderate (I\u0026sup2; = 26\u0026ndash;50%), or high (I\u0026sup2; \u0026gt; 50%). Confidence intervals (CI) for summary effects were calculated using Hartung\u0026ndash;Knapp\u0026ndash;Sidik\u0026ndash;Jonkman (HKSJ) when appropriate; otherwise, Wald or classic type depending upon the τ\u0026sup2; values, in accordance with Cochrane\u0026rsquo;s recommendation[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. A random-effects model was used for all analyses, irrespective of heterogeneity magnitude, due to anticipated clinical and methodological variability among studies. Statistical analyses were performed using RevMan web 9.17.0. Statistical significance was defined as a P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection and characteristics\u003c/h2\u003e \u003cp\u003eOur systematic search identified 228 records, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. After removal of duplicates and exclusion based on title and abstract screening, 20 full-text articles were assessed for eligibility. Ultimately, three RCTs (BALANCE,[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]CORE-TIMI 72a,[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] CORE-TIMI 72b[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]) were included in the meta-analysis, comprising a total of 1,127 patients, of whom 748 were assigned to the olezarsen group.\u003c/p\u003e \u003cp\u003eThe mean or median age ranged from 43.2 years to 55 years. Females accounted for 26% of the study population, and the follow-up duration was 12 months. Study characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, with additional details on baseline lipid profiles provided in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of included trials\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"14\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor, Year\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eI/C\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAge*\u003c/p\u003e \u003cp\u003e(yr)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003cp\u003e(kg/m\u0026sup2;)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDM\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eASCVD\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePancr.Hx\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eStatins\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eFibrates\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003eOmega-3\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003eFollow-up\u003c/p\u003e \u003cp\u003emonths\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eStroes et al., 2024\u003csup\u003e8\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOlez(80mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47.7\u0026thinsp;\u0026plusmn;\u0026thinsp;13.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11(50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7 (32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e17 (77.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e5 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e11 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e12 (55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOlez(50mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e43.2\u0026thinsp;\u0026plusmn;\u0026thinsp;12.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15(71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e22.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e15 (71.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4 (19.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e8(38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e6 (29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44.0\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12(52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6 (26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e15 (65.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e7 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e11 (48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e7 (30)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMarston et al., 2025\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eSHTG (CORE-TIMI 72a)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOlez(80m)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e204\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54 (45\u0026ndash;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e53 (26.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e31.2 (28.1\u0026ndash;34.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e127 (62.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e50 (24.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e43 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e153(75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e130(63.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e70(34.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOlez(50mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54 (45\u0026ndash;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e52 (25.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e31.2 (28.4\u0026ndash;35.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e128 (62.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e37 (18.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e51 (24.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e144(70.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e133(64.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e68(33.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54 (45\u0026ndash;62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e42 (20.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e30.9 (28.2\u0026ndash;34.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e113 (54.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e54 (26.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e48 (23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e147(70.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e146(70.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e70(33.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMarston et al., 2025\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eSHTG (CORE-TIMI 72b)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOlez (80 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e147\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55 (48\u0026ndash;62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37 (25.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e30.7 (27.7\u0026ndash;33.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e101 (68.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e45 (30.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e20 (13.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e115 (78.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e88 (59.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e38 (25.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOlez (50 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55 (48\u0026ndash;62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e39 (26.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e30.9 (27.9\u0026ndash;34.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e102 (68.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e41 (27.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e17 (11.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e111 (74.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e87 (58.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e46 (30.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54 (44\u0026ndash;62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27 (18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e32.2 (28.3\u0026ndash;36.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e102 (68.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e45 (30.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e21 (14.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e114(77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e90 (60.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e48 (32.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eASCVD: Atherosclerotic cardiovascular disease; BMI: Body mass index; DM: Diabetes mellitus; FCS: Familial chylomicronemia syndrome; I/C: intervention/Control; N: Number of subjects; Olez: Olezarsen; Omega3: Omega3 fatty acids; Pancr. Hx : Pancreatitis history; SHTG : Severe hypertriglyceridemia; Kg/m\u0026sup2;: Kilograms per square meter (Units for BMI); n(%): Number and percentage of subjects; yr: year\u003c/p\u003e \u003cp\u003e*\u0026plusmn; values represent mean and SD; otherwise, data in the table represent median and interquartile range or number (percentage)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline lipid profile of included trials\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor, Year\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eI/C\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTriglyceride\u003c/p\u003e \u003cp\u003e(mg/dL)*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eApolipoprotein C-III (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNon-HDL Cholesterol (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLDL Cholesterol (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eApolipoprotein B (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHDL Cholesterol (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eRemnant Cholesterol (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eStroes et al., 2024\u003csup\u003e8\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOlez (80 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2613\u0026thinsp;\u0026plusmn;\u0026thinsp;1499\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e262.9\u0026thinsp;\u0026plusmn;\u0026thinsp;100.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e22.8\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e58.4\u0026thinsp;\u0026plusmn;\u0026thinsp;17.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c10\"\u003e \u003cp\u003e14.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e245.7\u0026thinsp;\u0026plusmn;\u0026thinsp;110.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOlez (50 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2684\u0026thinsp;\u0026plusmn;\u0026thinsp;1235\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27.7\u0026thinsp;\u0026plusmn;\u0026thinsp;10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e307.6\u0026thinsp;\u0026plusmn;\u0026thinsp;101.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e17.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e65.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c10\"\u003e \u003cp\u003e15.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e293.2\u0026thinsp;\u0026plusmn;\u0026thinsp;103.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2596\u0026thinsp;\u0026plusmn;\u0026thinsp;1256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27.7\u0026thinsp;\u0026plusmn;\u0026thinsp;11.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e271.3\u0026thinsp;\u0026plusmn;\u0026thinsp;113.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e59.7\u0026thinsp;\u0026plusmn;\u0026thinsp;18.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c10\"\u003e \u003cp\u003e14.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e255.3\u0026thinsp;\u0026plusmn;\u0026thinsp;114.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMarston et al., 2025\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eSHTG (CORE-TIMI 72a)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOlez (80 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e204\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e810.0 (579.8\u0026ndash;1396.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e33.8 (25.5\u0026ndash;45.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e203.2 (160.8\u0026ndash;258.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e57.5 (37.2\u0026ndash;84.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e101.8 (81.0\u0026ndash;122.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c10\"\u003e \u003cp\u003e25.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e130.4 (82.2\u0026ndash;180.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOlez (50 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e845.5 (630.0\u0026ndash;1427.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34.6 (28.4\u0026ndash;50.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e197.5 (160.5\u0026ndash;252.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e59.0 (41.8\u0026ndash;83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e105.0 (88.2\u0026ndash;125.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c10\"\u003e \u003cp\u003e25.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e137.6 (97.3\u0026ndash;197.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e838.2 (606.2\u0026ndash;1233.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34.1 (26.1\u0026ndash;43.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e199.2 (161.0\u0026ndash;242.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e58.5 (41.0\u0026ndash;80.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e101.6 (87.1\u0026ndash;121.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c10\"\u003e \u003cp\u003e26.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e130.4 (92.7\u0026ndash;187.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMarston et al., 2025\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eSHTG\u003c/p\u003e \u003cp\u003e(CORE-TIMI 72b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOlez(80 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e147\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e750.5 (572.0\u0026ndash;1145.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34.1 (26.0\u0026ndash;43.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e186.0 (149.5\u0026ndash;241.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e60.0 (40.5\u0026ndash;81.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e101.5 (85.8\u0026ndash;120.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c10\"\u003e \u003cp\u003e27.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e125.0 (79.5\u0026ndash;199.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOlez(50 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e762.0 (600.5\u0026ndash;1114.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34.9 (28.0\u0026ndash;44.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e197.5 (159.0\u0026ndash;240.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e66.6 (44.8\u0026ndash;90.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e109.2 (93.9\u0026ndash;129.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c10\"\u003e \u003cp\u003e28.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e127.9 (87.0\u0026ndash;164.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e729.8 (577.0\u0026ndash;1097.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34.8 (27.1\u0026ndash;44.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e181.0 (147.0\u0026ndash;217.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e57.8 (39.2\u0026ndash;81.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e103.5 (81.7\u0026ndash;118.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c10\"\u003e \u003cp\u003e26.7\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e109.6 (76.8\u0026ndash;165.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003eFCS : Familial chylomicronemia syndrome; HDL Cholesterol: High-density lipoprotein cholesterol; I/C: Intervention/Control; LDL Cholesterol: Low-density lipoprotein cholesterol; N: Number of subjects; Non-HDL Cholesterol: Non-high density lipoprotein cholesterol; Olez: Olezarsen; SHTG: Severe hypertriglyceridemia\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e*\u0026plusmn; values represent mean and SD; otherwise, data in the table represent median and interquartile range.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eTG and apolipoprotein C-III at 6 and 12 months\u003c/h2\u003e \u003cp\u003eOlezarsen demonstrated a significant reduction in the mean percentage change from baseline in TG levels at 6 months (MD = -54.41%; 95% CI: -70.85, -37.97; P\u0026thinsp;=\u0026thinsp;.0004; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;81%) and at 12 months (MD = -54.37%; 95% CI: -61.19, -47.55; P\u0026thinsp;=\u0026thinsp;.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;21%), with an overall mean percentage change of -55.01% (95% CI: -61.97, -48.06; P\u0026thinsp;=\u0026thinsp;.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;62%; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) compared with placebo. Similarly, olezarsen was associated with a significant reduction in the mean percentage change from baseline in apolipoprotein C-III levels at 6 months (MD = -67.16%; 95% CI: -75.39, -58.94; P\u0026thinsp;=\u0026thinsp;.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;76%) and at 12 months (MD = -64.03%; 95% CI: -73.11, -54.95; P\u0026thinsp;=\u0026thinsp;.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;74%), with an overall mean percentage change of -65.66% (95% CI: -70.75, -60.57; P\u0026thinsp;=\u0026thinsp;.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;74%; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGiven the substantial heterogeneity observed across outcomes, leave-one-out sensitivity analyses were performed to assess the robustness of the pooled estimates and to explore potential sources of heterogeneity. These analyses identified the CORE-TIMI 72a trial\u003csup\u003e9\u003c/sup\u003e as the primary contributor to heterogeneity. After exclusion of this study, heterogeneity was significantly reduced for the mean percentage change in TG levels at 6 months (MD = -46.99%; 95% CI: -66.09, -27.89; P\u0026thinsp;=\u0026thinsp;.004; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;48%) and at 12 months (MD = -46.3%; 95% CI: -55.32, -42.53; P\u0026thinsp;=\u0026thinsp;.0002; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%), with an overall mean percentage change of -49.12% (95% CI: -54.87, -43.38; P\u0026thinsp;=\u0026thinsp;.00001; I\u003csup\u003e2\u003c/sup\u003e = %). Similar reductions in heterogeneity were observed for apolipoprotein C-III levels at 6 months (MD = -54.1%; 95% CI: -70.96, -52.46; P\u0026thinsp;=\u0026thinsp;.0002; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;23%) and at 12 months (MD = -57.65%; 95% CI: -69.04, -46.25; P\u0026thinsp;=\u0026thinsp;.0005; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;14%), with and overall mean percentage change of -59.83% (95% CI: -65.14, -54.52; P\u0026thinsp;=\u0026thinsp;.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;20%). These findings are presented in Supplementary Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e and Figure S2.\u003c/p\u003e \u003cp\u003eSensitivity analyses excluding patients with familial chylomicronemia syndrome demonstrated that statistically significant reductions in the mean percentage change from baseline in TG and apolipoprotein C-III levels persisted, although substantial heterogeneity remained (Supplementary Figure S3 and Figure S4).\u003c/p\u003e \u003cp\u003eSubgroup analyses evaluating dose-dependent effects showed significant reductions in TG levels at both the 50-mg dose (MD = -50.81; 95% CI: -63.28, -38.34; P\u0026thinsp;=\u0026thinsp;.0001; I\u0026sup2; = 64%) and the 80-mg dose (MD = -59.33%; 95% CI: -68.89, -49.77; P\u0026thinsp;=\u0026thinsp;.0001; I\u0026sup2; = 57%), with no significant subgroup difference (P\u0026thinsp;=\u0026thinsp;0.16; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003e In subgroup analysis, each row of the study represents a dose strength of 50 mg, first at 6 months and then at 12 months; similarly, this is the case with the 80 mg dose strength\u003c/p\u003e \u003cp\u003eSimilarly, apolipoprotein C-III levels were significantly reduced at both the 50-mg dose (MD = -63.11%; 95% CI: -71.22, -55.01; P\u0026thinsp;=\u0026thinsp;.00001; I\u0026sup2; = 69%) and the 80-mg dose (MD = -69.34%; 95% CI: -77.76, -60.92; P\u0026thinsp;=\u0026thinsp;.00001; I\u0026sup2; = 74%), with no significant subgroup difference (p\u0026thinsp;=\u0026thinsp;0.17; Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003eIn subgroup analysis, each row of the study represents a dose strength of 50 mg (a) first at 6 months and then (b) at 12 months; similarly, this is the case with the 80 mg dose strength.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eAcute pancreatitis\u003c/h2\u003e \u003cp\u003eOlezarsen was associated with a significant reduction in the incidence of acute pancreatitis compared with placebo (1.2% vs 8.7%; RR\u0026thinsp;=\u0026thinsp;0.14; 95% CI: 0.07, 0.29; P\u0026thinsp;=\u0026thinsp;.00001; I\u0026sup2; = 0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e), corresponding to an 86% relative risk reduction. Trial sequential analysis is shown in Supplementary Figure S5.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eOther lipid parameters\u003c/h2\u003e \u003cp\u003eOlezarsen was associated with a significant reduction in the mean percentage change from baseline in Non-high-density lipoprotein cholesterol (non-HDL-C) at 6 months (MD = -24.35%; 95% CI: -30.04, -18.66; P\u0026thinsp;=\u0026thinsp;.0001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;61%) and at 12 months (MD = -22.90%; 95% CI: -26.47, -19.32; P\u0026thinsp;=\u0026thinsp;.0001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%), with an overall mean percentage change of -23.92% (95% CI: -26.93, -20.91; P\u0026thinsp;=\u0026thinsp;.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;40%; Supplementary Figure S6).\u003c/p\u003e \u003cp\u003eA significant reduction in Remnant Cholesterol(RC) was also observed at 6 months (MD = -58.27%; 95% CI: -72.60, -43.95; P\u0026thinsp;=\u0026thinsp;.001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;71%) and at 12 months (MD = -52.20%; 95% CI: -61.43, -42.98; P\u0026thinsp;=\u0026thinsp;.0004; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%), with an overall mean percentage change of -55.30% ( 95% CI: -62.05, -48.56; P\u0026thinsp;=\u0026thinsp;.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;59%; Supplementary Figure S7).\u003c/p\u003e \u003cp\u003eMean percentage change in High density lipoprotein cholesterol(HDL-C) increased significantly at 6 months (MD\u0026thinsp;=\u0026thinsp;69.42%; 95% CI: 50.90, 87.94; P\u0026thinsp;=\u0026thinsp;.001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;82%) and at 12 months (MD\u0026thinsp;=\u0026thinsp;67.78%; 95% CI: 52.08, 83.48; P\u0026thinsp;=\u0026thinsp;.0008; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;73%), with an overall mean percentage change of 68.60% ( 95% CI: 60.22, 76.99; P\u0026thinsp;=\u0026thinsp;.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;75%; Supplementary Figure S8).\u003c/p\u003e \u003cp\u003eLDL Cholesterol(LDL-C) increased significantly in the olezarsen group at 6 months (MD\u0026thinsp;=\u0026thinsp;52.75%; 95% CI: 42.17, 63.33; P\u0026thinsp;=\u0026thinsp;.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;31%) and at 12 months (MD\u0026thinsp;=\u0026thinsp;46.1%; 95% CI: 43.74, 62.57; P\u0026thinsp;=\u0026thinsp;.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%), with an overall mean percentage change of 53.25% (95% CI: 46.85, 59.64; P\u0026thinsp;=\u0026thinsp;.00001; I\u0026sup2; = 0%; Supplementary Figure S9).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSafety parameters\u003c/h2\u003e \u003cp\u003eThe olezarsen group experienced a lower incidence of serious adverse events compared with placebo (RR\u0026thinsp;=\u0026thinsp;0.63; 95% CI: 0.41, 0.98; P\u0026thinsp;=\u0026thinsp;.04; I\u0026sup2; = 24%; Supplementary Figure S10A). There was no significant difference between groups in the incidence of any adverse events (RR\u0026thinsp;=\u0026thinsp;0.97; 95% CI: 0.88, 1.07; P\u0026thinsp;=\u0026thinsp;.55; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;41%; Supplementary Figure S10B)or in hepatic enzyme elevation, including AST\u0026thinsp;\u0026ge;\u0026thinsp;3x the upper limit of normal (RR\u0026thinsp;=\u0026thinsp;2.04; 95% CI: 0.83, 4.98; P\u0026thinsp;=\u0026thinsp;.12; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;6%; Supplementary Figure S10C) and ALT\u0026thinsp;\u0026ge;\u0026thinsp;3x the upper limit of normal (RR\u0026thinsp;=\u0026thinsp;0.72; 95% CI: 0.04, 13.72; P\u0026thinsp;=\u0026thinsp;.83; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;74%; Supplementary Figure S10D).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eGRADE assessment\u003c/h2\u003e \u003cp\u003eGRADE assessment for primary and clinically relevant outcomes was also done, which showed moderate tohigh certainty of evidence across outcomes, as shown in Supplementary Table S2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias assessment\u003c/h2\u003e \u003cp\u003eThe Risk of Bias 2 (RoB 2) tool was used to assess quality. No studies were considered to be at high risk of bias, as described in Supplementary Figure S11. In the funnel plot analysis, studies were distributed symmetrically by weight and converged toward the pooled effect as weight increased (Supplementary Figure S12 and Figure S13). Egger\u0026rsquo;s test was not performed because fewer than 10 studies were included (k\u0026thinsp;\u0026lt;\u0026thinsp;10).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e We conducted a systematic review and meta-analysis comprising 1,127 patients with SHTG. The main findings associated with olezarsen were significant reductions in: (1) the mean percentage change from baseline in TG levels at both 6 and 12 months, compared with placebo; (2) the mean percentage change from baseline in apolipoprotein C-III levels at both 6 and 12 months, compared with placebo; and (3) other lipid parameters, including non-HDL cholesterol and remnant cholesterol. Additionally, no significant difference in adverse events was observed between the treatment groups.\u003c/p\u003e \u003cp\u003eOlezarsen is an antisense oligonucleotide that targets messenger RNA (mRNA) encoding apolipoprotein C-III, thereby reducing apolipoprotein C-III production and lowering plasma triglyceride levels.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. TGs themselves are not inherently toxic to the pancreas; instead, pancreatic injury occurs when TGs are hydrolyzed by pancreatic lipase into free fatty acids (FFAs), leading to lipotoxicity[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Excess FFAs aggregate into detergent-like micelles that induce ischemia, promote acidosis, activate trypsinogen into trypsin, and ultimately result in pancreatic autodigestion.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious systematic reviews and meta-analyses have consistently shown reductions in TG and apolipoprotein C-III levels among hypertriglyceridemic patients[\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In one such review, the mean percentage reduction in TG levels was \u0026minus;\u0026thinsp;44.64%, and the reduction in apolipoprotein C-III was \u0026minus;\u0026thinsp;65.38%[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Our meta-analysis demonstrated a greater reduction in TGs (-55.01%) and a comparable reduction in apolipoprotein C-III (-65.66%). While consistent with prior findings, earlier reviews were limited by smaller sample sizes, underpowered clinical endpoints, inclusion of mixed patient populations, and the absence of pancreatitis as a systematically evaluated outcome. In contrast, our analysis included larger trials restricted to patients with SHTG, demonstrated low risk of bias, and evaluated pancreatitis as a clinically meaningful endpoint, showing a substantial relative risk reduction supported by trial sequential analysis.\u003c/p\u003e \u003cp\u003eWe observed a relative increase in LDL cholesterol of approximately 53%, which warrants mechanistic interpretation rather than immediate clinical concern[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. When TG concentrations are markedly reduced, accelerated lipolysis of TG-rich very-low-density lipoproteins (VLDL) and chylomicrons leads to the generation of LDL particles that carry liberated cholesteryl esters[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Importantly, this shift was accompanied by reductions in non-HDL cholesterol (-23.26%) and remnant cholesterol (-55.30%), lipid parameters that more accurately reflect atherogenic burden than LDL cholesterol alone in patients with SHTG[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The net transition from a chylomicron-dominant to an LDL-dominant lipoprotein profile is thought to improve cardiovascular risk, as remnant particles are inherently more inflammatory and prothrombotic than LDL particles[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Recent advances in human genetics further support targeting apolipoprotein C-III mRNA to reduce TG levels and cardiovascular risk. Individuals with loss-of-function variants in the APOC3 gene exhibit a lower risk of subclinical and overt atherosclerosis.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Conventional TG-lowering therapies, including pemafibrate, fenofibrate, niacin, and omega-3 fatty acids, have demonstrated efficacy in reducing TG levels but have failed to show consistent improvements in cardiovascular outcomes or safety signals[\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].In patients with SHTG, particularly those with FCS, the primary therapeutic goal is to reduce TG levels to prevent recurrent episodes of acute pancreatitis[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Fibrates and omega-3 fatty acids have not demonstrated efficacy in reducing pancreatitis risk in this population[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Our findings suggest that olezarsen provides a meaningful reduction in pancreatitis risk, offering a novel therapeutic option that may transform a recurrent, life-threatening condition into a manageable metabolic disorder.\u003c/p\u003e \u003cp\u003eThe study design and enrolment criteria varied among the included trials. For example, the BALANCE trial enrolled patients with genetically confirmed FCS[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], whereas the CORE-TIMI trials included patients with multifactorial SHTG[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, both populations share a common downstream pathophysiology characterized by impaired clearance of TG-rich lipoproteins mediated through the apolipoprotein C-III pathway. Because olezarsen directly targets this shared mechanism, pooling data across trials was considered clinically meaningful for lipid-lowering and pancreatitis-related outcomes. Anticipated heterogeneity was addressed using a random-effects model and prespecified sensitivity analyses stratified by FCS status.\u003c/p\u003e \u003cp\u003ePrior trials evaluating plozasiran for hypertriglyceridemia reported mild to moderate elevations in liver transaminases[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In contrast, our analysis did not identify significant liver-related adverse effects associated with olezarsen, suggesting a more favorable safety and tolerability profile. Olezarsen also appears to provide improved safety compared to Volesarsen, another apolipoprotein C-III mRNA inhibitor. While Volanesorsen is effective in treating hypertriglyceridemia, its use is limited by safety concerns, particularly thrombocytopenia, which requires regular platelet monitoring[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Olezarsen appears to mitigate these risks while maintaining effective TG reduction [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]Differences in molecular structure, binding specificity, and pharmacokinetics may explain its improved safety profile. Nonetheless, continued long-term monitoring remains essential to ensure sustained safety.\u003c/p\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eOur systematic review and meta-analysis has specific limitations that merit consideration. First, the analysis included only three RCTs, which limits the statistical power for rare safety events despite the robust efficacy signal. Second, the duration of follow-up in the included studies ranged from 6 to 12 months; long-term outcomes of lipid endpoints, pancreatitis, and cardiovascular mortality remained underexplored. Third, we observed substantial statistical heterogeneity in most outcomes, driven by differences in baseline characteristics and study design between the FCS and broader hypertriglyceridemia populations. Nevertheless, we performed a prespecified sensitivity analysis, and the results remained consistent across outcomes. Fourth, we have assessed the efficacy of olezarsen across both populations, but future trials are still needed to determine population-specific outcomes. Finally, while the increase in LDL cholesterol is mechanistically understood, the net effect of this change on long-term atherosclerotic plaque burden in this specific population remains to be empirically quantified in multi-year outcome trials.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis systematic review and meta-analysis of olezarsen in patients with SHTG demonstrated significant reductions in TG, apolipoprotein C-III, and other lipid parameters, including non-HDL and remnant cholesterol. Olezarsen was also associated with a reduced risk of acute pancreatitis, without an increase in adverse events. These findings support olezarsen as an effective therapeutic option for patients with SHTG.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eALT\u0026nbsp;\u003c/strong\u003eAlanine aminotransferase\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAPOC3\u0026nbsp;\u003c/strong\u003eApolipoprotein C-III gene\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAST\u0026nbsp;\u003c/strong\u003eAspartate aminotransferase\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eASCVD\u0026nbsp;\u003c/strong\u003eAtherosclerotic cardiovascular disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBMI\u0026nbsp;\u003c/strong\u003eBody mass index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCI\u0026nbsp;\u003c/strong\u003e Confidence interval\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDM\u0026nbsp;\u003c/strong\u003e Diabetes mellitus\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFCS\u0026nbsp;\u003c/strong\u003e Familial chylomicronemia syndrome\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFFA\u0026nbsp;\u003c/strong\u003eFree fatty acid\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGRADE\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp;Grading of Recommendations Assessment, Development and Evaluation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHDL\u0026nbsp;\u003c/strong\u003e\u0026nbsp; High-density lipoprotein\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHKSJ\u0026nbsp;\u003c/strong\u003e Hartung\u0026ndash;Knapp\u0026ndash;Sidik\u0026ndash;Jonkman method\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLDL\u0026nbsp;\u003c/strong\u003eLow-density lipoprotein\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNon-HDL\u0026nbsp;\u003c/strong\u003eNon\u0026ndash;high\u0026ndash;density lipoprotein\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eREML\u0026nbsp;\u003c/strong\u003eRestricted maximum likelihood\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRR\u0026nbsp;\u003c/strong\u003eRisk ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRoB 2\u0026nbsp;\u003c/strong\u003eRisk of Bias version 2 tool\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSHTG\u0026nbsp;\u003c/strong\u003eSevere hypertriglyceridemia\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTG \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003eTriglyceride\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eULN\u0026nbsp;\u003c/strong\u003eUpper limit of normal\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVLDL\u0026nbsp;\u003c/strong\u003eVery-low-density lipoprotein\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp; No funding and grant received to conduct this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e Data are available from the corresponding author\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eupon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e The authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a systematic review and meta-analysis of previously published studies. No new human or animal subjects were involved, and therefore institutional review board approval and informed consent were not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication ethics statement\u003c/strong\u003e The authors affirm adherence to the guidelines of the committee on publication ethics (COPE) and the recommendations of the international committee of medical journal editors (ICMJE), defining the role of authors and contributors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: A.R.;\u003c/p\u003e\n\u003cp\u003eData curation: A.R., D.R.;\u003c/p\u003e\n\u003cp\u003eFormal analysis: A.R., J.D.M.;\u003c/p\u003e\n\u003cp\u003eWriting\u0026mdash;original draft: A.R., J.D.M., J.L., D.R.;\u003c/p\u003e\n\u003cp\u003eWriting\u0026mdash;review and editing: A.R., J.D.M., J.L., D.R.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;All authors have approved the final article for submission.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMerkel M, M\u0026uuml;ller-Wieland D, Laufs U, Parhofer KG. 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Volanesorsen in the Treatment of Familial Chylomicronemia Syndrome or Hypertriglyceridaemia: Design, Development and Place in Therapy. \u003cem\u003eDDDT\u003c/em\u003e. 2020;Volume 14:2623\u0026ndash;2636.. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2147/DDDT.S224771\u003c/span\u003e\u003cspan address=\"10.2147/DDDT.S224771\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Olezarsen, Severe hypertriglyceridemia, pancreatitis, apolipoprotein C-III, non-HDL Cholesterol, remnant cholesterol","lastPublishedDoi":"10.21203/rs.3.rs-8583537/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8583537/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003e Olezarsen has shown efficacy in hypertriglyceridemic and dyslipidemic populations of mixed cohorts, but its effectiveness in severe hypertriglyceridemia(SHTG) is unknown.This is systematic review and meta-analysis to evaluate the efficacy of olezarsen in SHTG and associated risk of pancreatitis.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003ePubMed, Embase, and Cochrane databases were systematically searched for published trials comparing olezarsen vs. placebo in SHTG patients up to December 03, 2025. We computed mean difference (MD) and risk ratio (RR) with 95% CI for continuous and binary endpoints, respectively, using a random-effects model.Significance level was set with P-value(\u0026lt;\u0026thinsp;0.05)\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFrom 228 database records, three randomized trials involving a total of 1,127 patients were included. Of these, 748 patients (66.3%) received olezarsen. Olezarsen significantly reduced the mean percentage change from baseline of triglyceride (TG) levels (MD = -55.01%;95% CI: -61.97, -48.06; P\u0026thinsp;=\u0026thinsp;.00001), of apolipoprotein C-III levels (MD = -65.66%; 95% CI: -70.75, -60.57; P\u0026thinsp;=\u0026thinsp;.00001) compared to placebo. Significant reductions were also observed for other lipid parameters, specifically Non-high-density lipoprotein cholesterol (non-HDL-C) (MD = -23.92%;95% CI: -26.93, -20.91; P\u0026thinsp;=\u0026thinsp;.00001) and Remnant cholesterol(RC) (MD = -55.30%;95% CI: -62.05, -48.56; P\u0026thinsp;=\u0026thinsp;.00001) with reduced risk of acute pancreatitis (1.2% vs 8.7%; RR\u0026thinsp;=\u0026thinsp;0.14; 95% CI: 0.07, 0.29; P\u0026thinsp;=\u0026thinsp;.00001) compared to placebo. No significant adverse events were observed between groups.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOlezarsen significantly reduced TG, apolipoprotein C-III, and other lipid parameters while reducing acute pancreatitis risk without increasing adverse events. These findings are suggestive that olezarsen is an effective alternative therapy for patients with SHTG.\u003c/p\u003e","manuscriptTitle":"Efficacy of Olezarsen in severe hypertriglyceridemia and acute pancreatitis risk: A systematic review and meta-analysis of randomized controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-13 10:45:50","doi":"10.21203/rs.3.rs-8583537/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-11T23:56:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-02T14:40:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-27T13:58:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"236487036597556818098606093337979680646","date":"2026-01-17T21:57:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"57403422638744691002254904868068698298","date":"2026-01-14T15:35:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-14T14:35:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-13T20:25:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-13T12:23:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Digestive Diseases and Sciences","date":"2026-01-12T15:31:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f7566747-21ec-4b4f-a29e-4638b57fae47","owner":[],"postedDate":"January 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-23T16:01:54+00:00","versionOfRecord":{"articleIdentity":"rs-8583537","link":"https://doi.org/10.1007/s10620-026-09846-1","journal":{"identity":"digestive-diseases-and-sciences","isVorOnly":false,"title":"Digestive Diseases and Sciences"},"publishedOn":"2026-03-21 15:58:52","publishedOnDateReadable":"March 21st, 2026"},"versionCreatedAt":"2026-01-13 10:45:50","video":"","vorDoi":"10.1007/s10620-026-09846-1","vorDoiUrl":"https://doi.org/10.1007/s10620-026-09846-1","workflowStages":[]},"version":"v1","identity":"rs-8583537","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8583537","identity":"rs-8583537","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}