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Cited by 2Lipid metabolism and disordersLipoproteins and Cardiovascular HealthPancreatitis Pathology and Treatment

Efficacy of Olezarsen in Severe Hypertriglyceridemia and Acute Pancreatitis Risk: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Open access
Rehman, Abdul, Rajdeep, Dhvanit, Mohnkern, Jonathan D., Lin, Jacopo·2026·Digestive Diseases and Sciences
DOI 10.1007/s10620-026-09846-1

Published version of a preprint

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Abstract

Olezarsen has shown efficacy in hypertriglyceridemic and dyslipidemic populations of mixed cohorts, but its effectiveness in severe hypertriglyceridemia(SHTG) is unknown. This is a systematic review and meta-analysis to evaluate the efficacy of olezarsen in SHTG and the associated risk of pancreatitis. 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). From 228 database records, three randomized trials involving 1127 patients were included, with a 12-month follow-up. Of these, 748 patients (66.3%) received olezarsen. Olezarsen significantly reduced the mean percentage change from baseline of triglyceride (TG) levels, especially for the non–familial chylomicronemia syndrome(non-FCS) population (MD = − 59.95%; 95% CI − 76.00 to − 43.90; P = .001), of apolipoprotein C-III levels (MD = − 66.68%; 95% CI − 80.86 to − 52.69; P = .0006) at 6 months compared to placebo, albeit with significant heterogeneity. Significant reductions were also observed for other lipid parameters, specifically Non-high-density lipoprotein cholesterol (non-HDL-C) (MD = − 23.72%; 95% CI: − 27.35, − 20.09; P = .00001) and Remnant cholesterol(RC) (MD = − 55.30%;95% CI: − 62.05, -48.56; P = .00001) with an increase in LDL level. Olezarsen reduced the 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. Our analysis suggests olezarsen may be an effective therapeutic option in SHTG for reducing lipids and acute pancreatitis risk. However, its long-term safety and efficacy remain to be explored in future trials in this cohort.

AI snapshot

Written from the paper’s full text.

TL;DR

In this systematic review and meta-analysis of three RCTs (1,127 patients with severe hypertriglyceridemia), olezarsen significantly lowered triglycerides, apolipoprotein C-III, non-HDL cholesterol, and remnant cholesterol versus placebo and reduced acute pancreatitis incidence. It did not increase overall adverse events, though LDL cholesterol rose and long-term outcomes remain uncertain.

Key findings

  • Olezarsen reduced the mean percentage change from baseline in triglycerides overall (MD = -55.01%; 95% CI: -61.97, -48.06; P = .00001; I² = 62%) and apolipoprotein C-III overall (MD = -65.66%; 95% CI: -70.75, -60.57; P = .00001; I² = 74%) compared with placebo.
  • Non-HDL cholesterol fell overall (MD = -23.92%; 95% CI: -26.93, -20.91; P = .00001; I² = 40%) and remnant cholesterol fell overall (MD = -55.30%; 95% CI: -62.05, -48.56; P = .00001; I² = 59%), while LDL cholesterol increased overall (MD = 53.25%; 95% CI: 46.85, 59.64; P = .00001; I² = 0%).
  • Acute pancreatitis occurred in 1.2% of olezarsen patients vs 8.7% of placebo patients (RR = 0.14; 95% CI: 0.07, 0.29; P = .00001; I² = 0%), corresponding to an 86% relative risk reduction.
  • Serious adverse events were lower with olezarsen (RR = 0.63; 95% CI: 0.41, 0.98; P = .04; I² = 24%); any adverse events did not differ significantly (RR = 0.97; 95% CI: 0.88, 1.07; P = .55; I² = 41%), nor did AST ≥3x ULN (RR = 2.04; 95% CI: 0.83, 4.98; P = .12; I² = 6%) or ALT ≥3x ULN (RR = 0.72; 95% CI: 0.04, 13.72; P = .83; I² = 74%).

Methods

  • Systematic review and meta-analysis registered in PROSPERO (CRD420251243520); PubMed, Embase, and Cochrane were searched from database inception to December 3, 2025, following PRISMA and Cochrane Handbook guidance.
  • Three RCTs were included (BALANCE, CORE-TIMI 72a, CORE-TIMI 72b), totaling 1,127 patients; 748 (66.3%) received olezarsen. Mean or median age ranged from 43.2 to 55 years, females accounted for 26%, and follow-up duration was 12 months.
  • Random-effects meta-analysis used mean difference for continuous endpoints and risk ratio for binary endpoints with 95% CIs; heterogeneity was assessed with Cochran’s Q, I², and tau-square; leave-one-out and FCS-exclusion sensitivity analyses and dose subgroup analyses were performed using RevMan web 9.17.0, with significance set at P < 0.05.

Limitations

  • Stated: only three RCTs were included, limiting statistical power for rare safety events; follow-up ranged from 6 to 12 months, leaving long-term lipid, pancreatitis, and cardiovascular mortality outcomes underexplored; substantial heterogeneity was driven by differences between FCS and broader hypertriglyceridemia populations; future trials are needed for population-specific outcomes; and the net long-term effect of the LDL cholesterol increase on atherosclerotic plaque burden remains unquantified.
  • Evident: the pooled analysis combines BALANCE (genetically confirmed FCS) with CORE-TIMI trials (multifactorial SHTG), so results may not apply uniformly across SHTG subtypes; publication bias was assessed only by funnel plots, and Egger’s test was not performed because fewer than 10 studies were included.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s10620-026-09846-1

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

38 of 80 cited sources checked · 3 supported · 5 flagged · accuracy not yet measured

  • Findingown data

    Olezarsen significantly reduced the mean percentage change from baseline in non-HDL cholesterol at 12 months compared with placebo, with MD -22.90% (95% CI -26.47 to -19.32; P=.0001; I2=0%).

    “and at 12 months (MD = -22.90%;95% CI: -26.47, -19.32;P=.0001;I 2 = 0%)”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [8] Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E et al. Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome. N Engl J Med. 2024;390:1781–1792. https://doi.org/10.1056/NEJMoa2400201. source

      The End Points section (p. 4) identifies 12-month non-HDL cholesterol change as a secondary end point. But the Secondary End Points section (p. 8) explicitly says those results should not be interpreted as hypothesis tests, contrary to the claim of a statistically significant reduction. Our copy does not report the stated mean difference, confidence interval, P value, or I². (LLM, conf=0.84)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [9] Marston NA, Bergmark BA, Alexander VJ et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2512761. source
  • Findingown data

    Olezarsen significantly increased the mean percentage change from baseline in LDL cholesterol at 6 months compared with placebo, with MD 52.75% (95% CI 42.17 to 63.33; P=.00001; I2=31%).

    “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%)”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [8] Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E et al. Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome. N Engl J Med. 2024;390:1781–1792. https://doi.org/10.1056/NEJMoa2400201. source

      The Prespecified Exploratory End Points (p. 8) report higher mean LDL cholesterol levels at 6 months in the olezarsen groups, but the Discussion (p. 11) explicitly calls the increases “nonsignificant.” The paper does not report the claimed mean difference, confidence interval, P value, or I² for LDL cholesterol. (LLM, conf=0.92)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [9] Marston NA, Bergmark BA, Alexander VJ et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2512761. source
  • Findingown data

    In sensitivity analyses excluding patients with familial chylomicronemia syndrome, statistically significant reductions in the mean percentage change from baseline in triglyceride levels persisted.

    “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”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [8] Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E et al. Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome. N Engl J Med. 2024;390:1781–1792. https://doi.org/10.1056/NEJMoa2400201. source

      The Discussion (p. 11) states that only patients with genetically confirmed familial chylomicronemia syndrome were enrolled in this trial. The paper therefore could not have demonstrated that a triglyceride reduction persisted in a sensitivity analysis excluding those patients; its reported reduction concerns patients with the syndrome, not an excluded-FCS group. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [9] Marston NA, Bergmark BA, Alexander VJ et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2512761. source
  • Findingown data

    In dose subgroup analysis, olezarsen significantly reduced triglyceride levels at the 50-mg dose, with MD -50.81 (95% CI -63.28 to -38.34; P=.0001; I2=64%).

    “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%)”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [8] Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E et al. Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome. N Engl J Med. 2024;390:1781–1792. https://doi.org/10.1056/NEJMoa2400201. source

      The Primary Efficacy End Points (p. 5) explicitly report that the 50-mg dose did not significantly reduce triglycerides versus placebo at six months: −22.4 percentage points (95% CI, −47.2 to 2.5; P=0.08). The cited trial does not report the claimed subgroup estimate or I² statistic. (LLM, conf=0.89)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [9] Marston NA, Bergmark BA, Alexander VJ et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2512761. source
  • Findingown data

    In sensitivity analyses excluding patients with familial chylomicronemia syndrome, statistically significant reductions in the mean percentage change from baseline in apolipoprotein C-III levels persisted.

    “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”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [8] Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E et al. Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome. N Engl J Med. 2024;390:1781–1792. https://doi.org/10.1056/NEJMoa2400201. source

      The Discussion (p. 11) states that only patients with familial chylomicronemia syndrome were enrolled in the Balance trial. The trial therefore could not have produced a sensitivity analysis excluding those patients, regardless of its reported reductions in apolipoprotein C-III. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [9] Marston NA, Bergmark BA, Alexander VJ et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2512761. source
  • May combine two claims. 18
  • Classified as probably not a substantial claim. 8
  • The quote only partly states this claim. 3

  • May combine two claims.

    Findingown data

    Olezarsen was associated with a significant reduction in the incidence of acute pancreatitis compared with placebo, with 1.2% versus 8.7%, RR 0.14 (95% CI 0.07 to 0.29; P=.00001; I2=0%), corresponding to an 86% relative risk reduction.

    “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.”
    • Also stated in: § Acute pancreatitis · plain
      “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%; Figure 6), corresponding to an 86% relative risk reduction.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [8] Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E et al. Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome. N Engl J Med. 2024;390:1781–1792. https://doi.org/10.1056/NEJMoa2400201. source

      The Secondary End Points (p. 8) report fewer acute-pancreatitis episodes with pooled olezarsen than with placebo, supporting the direction of the claim. But the paper reports a rate ratio of 0.12 (95% CI, 0.02–0.66), not the cited percentages, RR of 0.14, confidence interval, P value, or I². It also says the secondary-end-point intervals were not adjusted for multiplicity and should not be interpreted as hypothesis tests, so the claim of a significant reduction overstates this trial's result. (LLM, conf=0.91)

      Experimental — accuracy not yet measured
    • cites [9] Marston NA, Bergmark BA, Alexander VJ et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2512761. source

  • May combine two claims.

    Premisecitation

    Conventional triglyceride-lowering therapies such as fibrates and omega-3 fatty acids often produce only modest reductions in triglyceride levels and have not been shown to reduce the risk of acute pancreatitis.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] Filtz A, Parihar S, Greenberg GS et al. New approaches to triglyceride reduction: is there any hope left? American Journal of Preventive Cardiology. 2024;18:100648. https://doi.org/10.1016/j.ajpc.2024.100648. source

      The Fibrates section (page unavailable) reports triglyceride reductions of 16%, 26%, and 31% in cited trials, and the Omega-3 Fatty Acids section identifies triglyceride reduction as an effect. But the Acute Pancreatitis section discusses risk from elevated triglycerides, not whether fibrates or omega-3 fatty acids have been shown to prevent pancreatitis; the paper therefore does not support that part of the claim. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Prior systematic reviews and meta-analyses of olezarsen in hypertriglyceridemic or dyslipidemic cohorts were limited by small sample sizes, underpowered individual endpoints, lack of restriction to severe hypertriglyceridemia, and absence of systematic evaluation of pancreatitis as a clinical outcome.

    “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][11][12][13].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [10] Ashraf T, Devi N, Aradhna F et al. The impact of olezarsen on hypertriglyceridemia in high cardiovascular risk patients: a systematic review, meta-analysis, and meta-regression. Ann Med Surg (Lond). 2025;87:5173–5184. https://doi.org/10.1097/MS9.0000000000003505. source

      In “Limitations and future research” (page unavailable), the review says its three included trials yielded a relatively small sample and restricted statistical power, and that it did not evaluate pancreatitis as a clinical outcome. Its Study selection criteria (page unavailable) do not restrict participants to severe hypertriglyceridemia. The paper does not specifically establish that individual endpoints were underpowered, so that part of the attributed claim goes beyond its findings. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [11] Serag I, Alkhawaldeh IM, Shati AA et al. Optimizing cardiovascular health: a systematic review and meta-analysis of olezarsen dosages in high-risk hypertriglyceridemic patients. Naunyn-Schmiedeberg’s Arch Pharmacol. 2025. https://doi.org/10.1007/s00210-025-04406-2. source
    • cites [12] Raja A, Shafique MA, Raja S et al. Olezarsen for hypertriglyceridemia in patients at high cardiovascular risk-a systematic review and meta analysis. Am J Ther. 2025;32:574–577. https://doi.org/10.1097/MJT.0000000000001877. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The study was conducted in accordance with PRISMA reporting guidelines.

    “Reviews and Meta-analyses (PRISMA) reporting guidelines [14,15].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [14] Page MJ, McKenzie JE, Bossuyt PM et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021. https://doi.org/10.1136/bmj.n71. source
    • cites [15] Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 6.5 Publisher: Cochrane 2024. https://www.cochrane.org/handbook

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Olezarsen is a hepatocyte-targeted, N-acetylgalactosamine-conjugated antisense oligonucleotide that binds apolipoprotein C-III messenger RNA, reducing apolipoprotein C-III synthesis and enhancing clearance of triglyceride-rich lipoproteins.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E et al. Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome. N Engl J Med. 2024;390:1781–1792. https://doi.org/10.1056/NEJMoa2400201. source

  • May combine two claims.

    Findingown data

    The meta-analysis included three randomized controlled trials comprising 1,127 patients, of whom 748 were assigned to olezarsen.

    “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.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [8] Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E et al. Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome. N Engl J Med. 2024;390:1781–1792. https://doi.org/10.1056/NEJMoa2400201. source
    • cites [9] Marston NA, Bergmark BA, Alexander VJ et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2512761. source

  • May combine two claims. The quote only partly states this claim.

    Interpretationcitation

    Olezarsen appears to provide improved safety compared with volanesorsen while maintaining effective triglyceride reduction.

    “Olezarsen appears to mitigate these risks while maintaining effective TG reduction [31][32][33]”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [30] Gaudet D, Clifton P, Sullivan D et al. RNA interference therapy targeting apolipoprotein C-III in hypertriglyceridemia. NEJM Evidence. 2023. https://doi.org/10.1056/EVIDoa2200325. source
    • cites [31] Kolovou G, Kolovou V, Katsiki N. Volanesorsen: a new Era in the treatment of severe hypertriglyceridemia. JCM. 2022;11:982. https://doi.org/10.3390/jcm11040982. source

      Section 2.2 reports triglyceride reductions with volanesorsen and safety concerns, including platelet-count declines. The paper does not report olezarsen’s safety or triglyceride-lowering efficacy, so it cannot support the claimed improvement over volanesorsen while maintaining effective reduction (searched: olezarsen and comparative safety). (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [32] Gaudet D, Brisson D, Tremblay K et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371:2200–2206. https://doi.org/10.1056/NEJMoa1400284. source

      The APOC3 Inhibition and Lipid Response section reports triglyceride reductions with ISIS 304801 in three patients, not with olezarsen. Searches for olezarsen, a safety comparison with volanesorsen, and adverse events found no passage in our copy addressing whether olezarsen mitigates those risks while retaining triglyceride-lowering efficacy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    After excluding CORE-TIMI 72a, heterogeneity was reduced for the mean percentage change in triglyceride levels at 6 months, with MD -46.99% (95% CI -66.09 to -27.89; P=.004; I2=48%).

    “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%)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Marston NA, Bergmark BA, Alexander VJ et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2512761. source

  • The quote only partly states this claim.

    Findingcitation

    After excluding CORE-TIMI 72a, heterogeneity was reduced for apolipoprotein C-III levels at 12 months, with MD -57.65% (95% CI -69.04 to -46.25; P=.0005; I2=14%).

    “and at 12 months (MD = -57.65%;95% CI: -69.04, -46.25;P=.0005;I 2 = 14%)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Marston NA, Bergmark BA, Alexander VJ et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2512761. source

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    After excluding CORE-TIMI 72a, heterogeneity was reduced for apolipoprotein C-III levels at 6 months, with MD -54.1% (95% CI -70.96 to -52.46; P=.0002; I2=23%).

    “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%)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Marston NA, Bergmark BA, Alexander VJ et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2512761. source

  • May combine two claims.

    Findingown data

    After excluding CORE-TIMI 72a, heterogeneity was reduced for the mean percentage change in triglyceride levels at 12 months, with MD -46.3% (95% CI -55.32 to -42.53; P=.0002; I2=0%).

    “and at 12 months (MD = -46.3%;95% CI: -55.32, -42.53;P=.0002;I 2 = 0%)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Marston NA, Bergmark BA, Alexander VJ et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2512761. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Risk of bias evaluation was performed independently by two authors, with disagreements resolved by consensus.

    “The risk of bias evaluation was performed independently by two authors (A.R., D.R.), with disagreements resolved by consensus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    In funnel plot analysis, studies were distributed symmetrically by weight and converged toward the pooled effect as weight increased.

    “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).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    A random-effects model was used for all analyses irrespective of heterogeneity magnitude because of anticipated clinical and methodological variability among studies.

    “A random-effects model was used for all analyses, irrespective of heterogeneity magnitude, due to anticipated clinical and methodological variability among studies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Egger's test was not performed because fewer than 10 studies were included.

    “Egger's test was not performed because fewer than 10 studies were included (k<10).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Two authors independently extracted data using standardized spreadsheets, with discrepancies resolved by consensus.

    “Two authors (A.R. and D.R.) independently extracted the data using standardized spreadsheets, with discrepancies resolved by consensus.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    This systematic review with meta-analysis was registered in PROSPERO under protocol number CRD420251243520.

    “This systematic review with meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under protocol number CRD420251243520.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The 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.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    A prespecified sensitivity analysis was performed, and the results remained consistent across outcomes.

    “Nevertheless, we performed a prespecified sensitivity analysis, and the results remained consistent across outcomes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The analysis included only three randomized controlled trials, which limits statistical power for rare safety events despite the robust efficacy signal.

    “First, the analysis included only three RCTs, which limits the statistical power for rare safety events despite the robust efficacy signal.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Anticipated heterogeneity was addressed using a random-effects model and prespecified sensitivity analyses stratified by familial chylomicronemia syndrome status.

    “Anticipated heterogeneity was addressed using a random-effects model and prespecified sensitivity analyses stratified by FCS status.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Olezarsen significantly reduced triglycerides, apolipoprotein C-III, and other lipid parameters while reducing acute pancreatitis risk without increasing adverse events.

    “Olezarsen significantly reduced TG, apolipoprotein C-III, and other lipid parameters while reducing acute pancreatitis risk without increasing adverse events.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The duration of follow-up in the included studies ranged from 6 to 12 months, and long-term outcomes of lipid endpoints, pancreatitis, and cardiovascular mortality remained underexplored.

    “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.”
    Quote in the paperNot a substantial claim
24 of 24

  • The paper relies on this without support.

    The familial chylomicronemia syndrome and non-familial-chylomicronemia severe hypertriglyceridemia populations share a common downstream pathophysiology characterized by impaired clearance of triglyceride-rich lipoproteins mediated through the apolipoprotein C-III pathway.

    “However, both populations share a common downstream pathophysiology characterized by impaired clearance of TG-rich lipoproteins mediated through the apolipoprotein C-III pathway.”
1 of 1

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting non-HDL cholesterol reduction

    Minor

    The Discussion gives a reduction of 23.26%, but the Results report an overall reduction of 23.92%.

  • Apolipoprotein C-III sensitivity-analysis estimate is not centered in its confidence interval

    Minor

    The confidence-interval bounds have a midpoint of −61.71%, substantially different from the reported mean difference of −54.1%.

    Reported -54.1 · recomputed -61.71

  • Conflicting counts of full-text articles assessed

    Minor

    The Results state that 20 full-text articles were assessed, whereas the Figure 1 caption states that 30 were assessed.

  • 12-month LDL cholesterol estimate is not centered in its confidence interval

    Minor

    The bounds 43.74% and 62.57% have a midpoint of 53.155%, rather than the reported mean difference of 46.1%.

    Reported 46.1 · recomputed 53.155

  • TG sensitivity-analysis estimate is not centered in its confidence interval

    Minor

    For a mean difference, the reported confidence interval should be centered on its estimate under the stated methods. The bounds −55.32 and −42.53 have a midpoint of −48.925, not the reported −46.3.

    Reported -46.3 · recomputed -48.925

5 of 5

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 6.5 (2024) (version 7.3, Chapter 10, Section 10.4.4). In: Publisher: Cochrane 2024. https://www.cochrane.org/handbook
  2. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 6.5 (2024) (version 7.3, Chapter 10, Section 10.3). In: Publisher: Cochrane 2024. https://www.cochrane.org/handbook

Cited by

Sorted by citations

Authors
Rehman, A., Rajdeep, D., Mohnkern, J. D., & Lin, J.
Affiliations
  • Rawalpindi Medical University (PK)
  • Caucasus International University (GE)
  • SUNY Upstate Medical University (US)
  • Vita-Salute San Raffaele University (IT)
Corresponding author
Rehman, Abdul
ORCID
Venue
Digestive Diseases and Sciences
Publisher
Springer Science and Business Media LLC
Published
2026-03-21
Volume
71
Issue
8
Pages
3832-3843
ISSN
  • 0163-2116 (ISSN-L)
  • 1573-2568
DOI
10.1007/s10620-026-09846-1
OpenAlex
W7139997530
Semantic Scholar
bb4114227d52432e4ea4ff558d28c3a9673b0222
Cited by
2
References
31
Citations by year
2026: 2
FWCI
4.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Digestive Diseases and Sciences (publishedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
Keywords
olezarsen, severe hypertriglyceridemia, acute pancreatitis, triglyceride lowering, apolipoprotein C-III, non-HDL cholesterol, remnant cholesterol, LDL cholesterol, lipid-lowering therapy, drug safety, dyslipidemia, nonsteroidal anti-inflammatory drugs, statins, fibrates
MeSH terms
Humans, Oligonucleotides, Pancreatitis, Triglycerides, Hypertriglyceridemia, Randomized Controlled Trials as Topic, Treatment Outcome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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