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Cited by 6Lipoproteins and Cardiovascular HealthLipid metabolism and disordersDiabetes, Cardiovascular Risks, and Lipoproteins

The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis

Open access
Sydhom, Pishoy, Al-Quraishi, Bakr, Gohar, Aya, El-Shawaf, Mohamad, Shehata, Nahla, Ataya, Miral, Sydhom, Mark, Awwad, Nouran +3 more·2026·Cardiovascular Drugs and Therapy
DOI 10.1007/s10557-025-07798-8PMC PMC13171978
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Abstract

Purpose: Emerging lipid-lowering therapies, such as Plozasiran, target apolipoprotein C-III (APOC-III) by inhibiting its hepatic production at the mRNA level, presenting a novel approach to lipid regulation. However, the safety and efficacy of plozasiran have yet to be fully established. Methods: We searched PubMed, Scopus, Web of Science, and Cochrane CENTRAL register of trials for studies comparing plozasiran to placebo in patients with dyslipidemic disorders. The primary outcomes were percentage changes from baseline in triglyceride (TG) and APOC-III levels at 24 weeks and the end of the study. Secondary outcomes included changes in other lipid parameters and safety outcomes at 24 weeks and the end of the study. A protocol was registered to PROSPERO under registration number [CRD420251026605]. Results: Four studies encompassing 1,514 participants were included in our meta-analysis. Plozasiran significantly improved TGs, APOC-III, non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels at both 24 weeks and study completion. Subgroup analyses based on dose and regimen revealed consistent findings. Quarterly administration of plozasiran at 10 mg, 25 mg, and 50 mg resulted in significant reductions in TGs, APOC-III, non–HDL-C, and HDL-C at both 24 weeks and study completion. For ApoB, all three doses produced significant reductions at 24 weeks; however, only the 25 mg and 50 mg quarterly regimens sustained these reductions through the end of the study. Regarding safety, patients receiving plozasiran experienced a higher incidence of any adverse events, headache, and mild rises in HbA1C levels. Subgroup analysis revealed a dose-dependent pattern for certain safety outcomes. Conclusion: While Plozasiran shows strong potential as a therapeutic option for severe dyslipidemic conditions, further studies are needed to compare its efficacy and safety with currently available treatments and, more importantly, evaluate its impact on clinical outcomes for implementation in clinical practice.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review and meta-analysis of four RCTs found that plozasiran significantly improved TG, APOC-III, non-HDL-C, HDL-C, and ApoB levels versus placebo in dyslipidemic disorders, with no significant LDL-C effect. Safety signals included more any adverse events, headache, and mild HbA1c/ALT increases, while serious adverse events and discontinuations did not differ significantly.

Key findings

  • Across 4 RCTs and 1,514 participants (534 plozasiran, 980 placebo), plozasiran reduced TG at 24 weeks (MD = −53.22, 95% CI [−57.17, −49.26], P < 0.00001) and study end (MD = −53.00, 95% CI [−60.51, −45.50], P < 0.00001), and reduced APOC-III at 24 weeks (MD = −72.21, 95% CI [−79.58, −64.83], P < 0.00001) and study end (MD = −65.42, 95% CI [−76.04, −54.81], P < 0.00001).
  • Plozasiran increased HDL-C at 24 weeks (MD = 43.99, 95% CI [37.51, 50.47], P < 0.00001) and study end (MD = 36.73, 95% CI [27.79, 45.67], P < 0.00001), and reduced non-HDL-C at 24 weeks (MD = −21.35, 95% CI [−25.14, −17.55], P < 0.00001) and study end (MD = −21.56, 95% CI [−26.69, −16.42], P < 0.00001). ApoB also fell at 24 weeks (MD = −11.61, 95% CI [−15.15, −8.07], P < 0.00001) and study end (MD = −9.89, 95% CI [−13.19, −6.59], P < 0.00001), while LDL-C did not differ significantly at either time point.
  • Quarterly plozasiran 10 mg, 25 mg, and 50 mg significantly reduced TG, APOC-III, non-HDL-C, and increased HDL-C at both 24 weeks and study end; for ApoB, all three doses reduced ApoB at 24 weeks, but only 25 mg and 50 mg quarterly sustained reductions at study end. The 50 mg quarterly regimen showed the greatest efficacy across lipid parameters.
  • Safety: any adverse events were higher with plozasiran (RR = 1.11, 95% CI [1.03, 1.19], P = 0.005), as were headache (RR = 1.85, 95% CI [1.14, 3.02], P = 0.01), HbA1c at 24 weeks (MD = 0.16, 95% CI [0.03, 0.30], P = 0.02) and study end (MD = 0.19, 95% CI [0.06, 0.31], P = 0.005), and ALT at 24 weeks (MD = 4.81, 95% CI [3.41, 6.20], P < 0.00001) and study end (MD = 3.98, 95% CI [0.88, 7.08], P = 0.01). Serious adverse events, discontinuation due to adverse events, COVID-19, URTI, AST, and platelet count did not differ significantly.

Methods

  • Systematic review and meta-analysis following PRISMA 2020 and Cochrane Handbook, prospectively registered with PROSPERO (CRD420251026605); searched PubMed, Scopus, Web of Science, and Cochrane CENTRAL from inception to February 19, 2025.
  • Included randomized clinical trials comparing plozasiran with placebo in patients with dyslipidemic disorders; 4 RCTs met eligibility criteria, encompassing 1,514 participants (534 plozasiran, 980 placebo), mean age 55.1 years, approximately 63% male.
  • Analysis used RevMan 5.4.1; risk ratios for dichotomous outcomes and mean differences with 95% CIs for continuous outcomes; random-effects model when chi-square P < 0.1, leave-one-out testing for heterogeneity, and subgroup analyses by dose (10, 25, 50, 100 mg) and regimen (monthly, quarterly, half-yearly). Risk of bias was assessed with Cochrane RoB 2.0, with all included studies rated low overall risk of bias.

Limitations

  • The authors state substantial heterogeneity across many outcomes due to variability in study populations, dosing, and administration regimens, only partly addressed by 24-week and dose/regimen subgroup analyses.
  • The authors state they could not directly assess clinical outcomes such as cardiovascular events because such data were unavailable, and that limited drug duration and short follow-up in some studies may underestimate long-term safety risks.
  • Evident from the text: only four RCTs were included; publication bias could not be assessed due to the limited number of studies; several subgroup analyses were based on single-study data, and some included trials had open-label extension periods.

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

Integrity signals

Registry

Crossref · 10.1007/s10557-025-07798-8

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

25 of 65 cited sources checked · 4 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Plozasiran reduces hepatic APOC-III production by inhibiting mRNA transcription.

    “Plozasiran, a siRNA-based therapeutic, reduces hepatic APOC-III production by inhibiting mRNA transcription [15].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371(23):2200–6. https://doi.org/10.1056/NEJMoa1400284. source

      The introductory passage identifies the studied drug as ISIS 304801, an antisense inhibitor—not plozasiran, a siRNA therapeutic. It says ISIS 304801 binds APOC3 mRNA and triggers its degradation by RNase H1, rather than inhibiting mRNA transcription. Our copy makes no claim about plozasiran itself. (LLM, conf=0.83)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Severe hypertriglyceridemia (≥500 mg/dL) is associated with serious non-cardiovascular complications, including non-alcoholic fatty liver disease, steatohepatitis, and acute pancreatitis.

    “Furthermore, severe hypertriglyceridemia (≥ 500 mg/dL) is associated with serious non-cardiovascular complications, including non-alcoholic fatty liver disease, steatohepatitis, and acute pancreatitis [11, 12].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [11] Pejic RN, Lee DT, Hypertriglyceridemia. The Journal of the American Board of Family Medicine [Internet]. 2006 May 1 [cited 2025 Apr 16];19(3):310–6. Available from: https://www.jabfm.org/content/19/3/310. source

      The Clinical Presentation section says hypertriglyceridemia above 500 mg/dL may cause pancreatitis. The paper also says pancreatitis risk does not become clinically significant until levels exceed 1000 mg/dL. Our copy does not link hypertriglyceridemia to non-alcoholic fatty liver disease or steatohepatitis (searched those terms and fatty liver/NASH). (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [12] Hegele RA, Ginsberg HN, Chapman MJ et al. The polygenic nature of hypertriglyceridaemia: Implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol [Internet]. 2014 Aug 1 [cited 2025 Apr 16];2(8):655–66. Available from: https://www.thelancet.com/action/showFullText?pii=S2213858713701918. source

      The Introduction and the Management section identify severe hypertriglyceridaemia as a risk factor for acute pancreatitis, but define severe as >10 mmol/L (>885 mg/dL), not ≥500 mg/dL. The Secondary causes section describes non-alcoholic fatty liver disease as a factor associated with increased risk of hypertriglyceridaemia, not as its complication; no passage found supports steatohepatitis as a complication. Page numbers were unavailable in our copy. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
  • Premisecitation

    Currently available therapies are not effective enough to reach guideline-recommended therapeutic goals in acquired severe hypertriglyceridemia.

    “Moreover, currently available therapies haven’t been effective enough to reach guideline-recommended therapeutic goals in acquired severe hypertriglyceridemia [5, 7, 8].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [5] Falko JM. Familial chylomicronemia syndrome: A clinical guide for endocrinologists. Endocr Pract. 2018;24(8):756–63. source
    • cites [7] Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease. Circ Res. 2016;118(4):547–63. https://doi.org/10.1161/CIRCRESAHA.115.306249. source

      The Abstract (page unavailable) says guidelines recommend lowering severely elevated triglycerides to reduce pancreatitis risk. It does not say whether available therapies achieve those goals, and searches for acquired severe hypertriglyceridemia and treatment targets found no passage addressing their effectiveness. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [8] Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J. 2020;41(1):99–109c. https://doi.org/10.1093/eurheartj/ehz785. source

      The ‘Therapy—approved pharmacologic treatments’ section reports limited evidence that adding triglyceride-lowering drugs to statins reduces cardiovascular risk, and notes that triglycerides can remain elevated despite lifestyle changes and attainment of an LDL-C goal. It does not establish that available therapies generally fail to achieve guideline-recommended goals specifically in acquired severe hypertriglyceridemia. Page numbers were not provided in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Premisecitation

    Nearly all VLDL particles containing APOC-III undergo intravascular triglyceride lipolysis, generating LDL particles that also contain APOC-III.

    “Studies have shown that nearly all VLDL particles containing APOC-III undergo intravascular triglyceride lipolysis, generating LDL particles that also contain APOC-III [25–27].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [25] Zheng C, Khoo C, Furtado J, Sacks FM. Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype. Circulation. 2010;121(15):1722–34. https://doi.org/10.1161/CIRCULATIONAHA.109.875807. source

      The Results (page not supplied) report that fewer than 7% of VLDL and IDL containing apoC-III but not apoE were removed before conversion to LDL, supporting near-complete conversion for that subgroup. The claim extends this to all apoC-III–containing VLDL, whereas the Discussion says apoE-containing triglyceride-rich particles mostly undergo direct removal. The Results also say that more than 80% of the resulting apoC-III–containing LDL was subsequently converted to LDL without apoC-III. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [26] Zheng C, Khoo C, Ikewaki K, Sacks FM. Rapid turnover of apolipoprotein C-III-containing triglyceride-rich lipoproteins contributing to the formation of LDL subfractions. J Lipid Res. 2007;48(5):1190–203. source

      The Results section on TRLs with apoC-III but not apoE reports that lipolysis can produce LDL that retains apoC-III. But it reports that only 70% of those TRLs reach LDL, with just 20% producing apoC-III-containing LDL; the Results section on TRLs containing both apoE and apoC-III says only 10% reach LDL. The claim overstates both how many apoC-III-containing particles become LDL and how often the resulting LDL retains apoC-III. (LLM, conf=0.92)

      Experimental — accuracy not yet measured
    • cites [27] Mendivil CO, Zheng C, Furtado J, Lel J, Sacks FM. Metabolism of very-low-density lipoprotein and low-density lipoprotein containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol. 2010;30(2):239–45. https://doi.org/10.1161/ATVBAHA.109.197830. source

      The Abstract’s Methods and Results report lipolytic conversion of APOC-III-containing VLDL and minimal direct removal from circulation, supporting conversion toward LDL. But the Discussion reports that some particles shed APOC-III during conversion, so the paper does not establish that nearly all such VLDL generate LDL that still contains APOC-III. Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    VLDL and LDL particles carrying APOC-III-but not those lacking APOC-III-initiate atherosclerosis by promoting endothelial injury and monocyte adhesion.

    “Moreover, VLDL and LDL particles carrying APOC-III—but not those lacking APOC-III—initiate atherosclerosis by promoting endothelial injury and monocyte adhesion [28, 29].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [28] Kawakami A, Aikawa M, Libby P, et al. Apolipoprotein CIII in apolipoprotein B lipoproteins enhances the adhesion of human monocytic cells to endothelial cells. Circulation. 2006;113(5):691–700. https://doi.org/10.1161/CIRCULATIONAHA.105.591743. source
    • cites [29] Kawakami A, Aikawa M, Alcaide P, et al. Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells. Circulation. 2006;114(7):681–7. https://doi.org/10.1161/CIRCULATIONAHA.106.622514. source

      The Results section (“VLDL CIII+ Induces Adhesion of THP-1 Cells to ECs”; page unavailable) reports that APOC-III-containing VLDL increased monocytic-cell adhesion to endothelial cells, whereas VLDL lacking APOC-III did not. The Abstract and Discussion describe endothelial activation and say APOC-III-rich VLDL *may contribute* to atherogenesis. This paper does not establish that both VLDL and LDL initiate atherosclerosis through endothelial injury; its direct endothelial comparison concerns VLDL, and it reports activation rather than injury. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 16
  • May combine two claims. 30
  • The quote only partly states this claim. 7

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

    Study design and conductcitation

    The systematic review and meta-analysis were performed according to PRISMA 2020 and adhered to the Cochrane Handbook of Systematic Reviews of Interventions.

    “This systematic review and meta-analysis were performed according to the Preferred Reporting Guidelines for Systematic Reviews and Meta-Analyses (PRISMA) 2020 [18] and adhered to the Cochrane Handbook of Systematic Reviews of Interventions [19].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [18] Page MJ, McKenzie JE, Bossuyt PM et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ [Internet]. 2021 Mar 29 [cited 2025 Apr 16];372. Available from: https://www.bmj.com/content/372/bmj.n71. source
    • cites [19] Higgins JPT, Thomas J, Chandler J, Cochrane handbook for systematic reviews of interventions IF: NA NA NA. dariososafoula.wordpress.comJ Chandler, Cumpston M, Li T, Page MJ et al. V WelchHoboken: Wiley, 2019•dariososafoula.wordpress.com [Internet]. 2019 [cited 2025 Apr 16]; Available from: https://dariososafoula.wordpress.com/wp-content/uploads/2017/01/cochrane-handbook-for-systematic-reviews-of-interventions-2019-1.pdf.

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

  • May combine two claims.

    Premisecitation

    All forms of dyslipidemia significantly increase the risk of atherosclerotic cardiovascular disease and all-cause mortality, primarily due to elevated LDL-C, triglycerides, triglyceride-rich lipoproteins, and their remnants.

    “All forms of dyslipidemia significantly increase the risk of atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality, primarily due to elevated LDL-C levels, triglycerides (TGs), triglyceride-rich lipoproteins (TRLs), and their remnants [7].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease. Circ Res. 2016;118(4):547–63. https://doi.org/10.1161/CIRCRESAHA.115.306249. source

      The Abstract reports that triglyceride-rich lipoproteins predict ASCVD and all-cause mortality, and that remnant cholesterol predicts ASCVD. But the paper does not support the claim about *all* forms of dyslipidemia: its Abstract says low HDL cholesterol is unlikely to cause ASCVD, and its Biology section describes severe hypertriglyceridemia without increased atherosclerosis. It also distinguishes LDL-related cholesterol from triglycerides in its discussion of all-cause mortality. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    A fasting triglyceride level above 150 mg/dL is a marker of increased atherosclerotic cardiovascular disease risk.

    “A fasting TG level above 150 mg/dL (1.69 mmol/L) is widely recognized as a marker of increased ASCVD risk [9, 10].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [9] Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459–72. https://doi.org/10.1093/eurheartj/ehx144. source

      The 'Evidence from prospective epidemiologic studies' section mentions triglycerides only as a measurement used in calculating or modeling LDL-C. Searches for fasting triglycerides, 150 mg/dL, and hypertriglyceridemia found no passage identifying that threshold as a marker of increased ASCVD risk. Page numbers were not available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [10] Stone NJ, Robinson JG, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the american college of cardiology/american heart association task force on practice guidelines. Circulation [Internet]. 2014 Jun 24 [cited 2025 Apr 16];129(25 SUPPL. 1):1–45. Available from: https://www.ahajournals.org/doi/https://doi.org/10.1161/01.cir.0000437738.63853.7a. source

  • May combine two claims.

    Premisereasoning

    In familial chylomicronemia syndrome, standard lipid-lowering therapies such as fibrates and omega-3 fatty acids are largely ineffective, and statins often fail to achieve adequate triglyceride reduction.

    “The absence of LPL activity renders standard lipid-lowering therapies—such as fibrates and omega-3 fatty acids—largely ineffective. Similarly, statins often fail to achieve adequate TG reduction in these patients.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [5] Falko JM. Familial chylomicronemia syndrome: A clinical guide for endocrinologists. Endocr Pract. 2018;24(8):756–63. source
    • cites [7] Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease. Circ Res. 2016;118(4):547–63. https://doi.org/10.1161/CIRCRESAHA.115.306249. source

      The Biology section (page not provided) says chylomicronemia caused by lipoprotein lipase deficiency involves no triglyceride degradation in plasma, supporting the sentence’s premise. It does not say that fibrates or omega-3 fatty acids are ineffective in these patients, or that statins fail to reduce their triglycerides adequately. The Randomized Trials section discusses these drugs in other populations, not their efficacy in familial chylomicronemia. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [8] Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J. 2020;41(1):99–109c. https://doi.org/10.1093/eurheartj/ehz785. source

      The section ‘Therapy—approved pharmacologic treatments’ says LDL-lowering drugs have only moderate effects on triglycerides, which lends limited support to the point about statins. The review also explains the role of LPL in triglyceride clearance (‘Triglyceride-rich lipoproteins metabolism in disease states’), but the passages found do not say that fibrates or omega-3 fatty acids are largely ineffective, or that statins often fail to achieve adequate triglyceride reduction, specifically in familial chylomicronemia syndrome. No page numbers were provided in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

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

    Study design and conductcitation

    The quality of included randomized controlled trials was assessed using the Cochrane Risk of Bias 2.0 tool, with two reviewers independently performing assessments and discrepancies resolved through consensus.

    “The quality of randomized controlled trials was assessed using the Cochrane Risk of Bias 2.0 (RoB 2) tool [21]. Two reviewers independently performed the assessments, and discrepancies were resolved through consensus.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [21] Sterne JAC, Savović J, Page MJ et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ [Internet]. 2019 Aug 28 [cited 2025 Apr 16];366. Available from: https://www.bmj.com/content/366/bmj.l4898. source

  • May combine two claims.

    Premisecitation

    These guideline-recommended approaches have shown limited efficacy in reducing triglyceride levels and preventing acute pancreatitis in clinical trials.

    “However, these approaches have shown limited efficacy in reducing triglyceride levels and preventing acute pancreatitis in clinical trials [8, 36, 37].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [8] Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J. 2020;41(1):99–109c. https://doi.org/10.1093/eurheartj/ehz785. source

      The 'Therapy—approved pharmacologic treatments' section says there are no high-quality trial data demonstrating that triglyceride-lowering therapy reduces acute pancreatitis risk. That is an evidence gap, not a finding of limited efficacy in clinical trials. The treatment table in 'Therapy of acute pancreatitis associated with high triglyceride' also says fibrates, omega-3 fatty acids, and niacin may lower triglycerides by up to 70%, so the broad claim of limited triglyceride reduction is not supported. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [36] Baass A, Paquette M, Bernard S, Hegele RA. Familial chylomicronemia syndrome: an under-recognized cause of severe hypertriglyceridaemia. J Intern Med [Internet]. 2020 Apr 1 [cited 2025 Apr 16];287(4):340–8. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/joim.13016 source
    • cites [37] Dron JS, Hegele RA. Genetics of Hypertriglyceridemia. Front Endocrinol (Lausanne). 2020 Jul 24;11:538521. source

      The Defining Hypertriglyceridemia section (page unavailable) describes how pancreatitis risk rises with triglyceride levels, but does not assess treatment efficacy. Searches for guideline-recommended treatments, triglyceride reduction, pancreatitis prevention, and clinical trials found no passage in our copy reporting that these approaches had limited efficacy. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Non-HDL cholesterol and ApoB are important predictors of ASCVD risk.

    “This is particularly relevant given the growing body of evidence indicating that non–HDL cholesterol and ApoB are important predictors of ASCVD risk [38, 39].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [38] Hansen MK, Mortensen MB, Warnakula Olesen KK, Thrane PG, Maeng M. Non-HDL cholesterol and residual risk of cardiovascular events in patients with ischemic heart disease and well-controlled LDL cholesterol: a cohort study. The Lancet Regional Health - Europe [Internet]. 2024 Jan 1 [cited 2025 Apr 16];36. Available from: https://www.thelancet.com/action/showFullText?pii=S266677622300193X source
    • cites [39] Johannesen CDL, Mortensen MB, Langsted A, Nordestgaard BG. Apolipoprotein B and Non-HDL Cholesterol Better Reflect Residual Risk Than LDL Cholesterol in Statin-Treated Patients. J Am Coll Cardiol [Internet]. 2021 Mar 23 [cited 2025 Apr 16];77(11):1439–50. Available from: https://www.jacc.org/doi/10.1016/j.jacc.2021.01.027 source

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

    Premisecitation

    Current guideline-recommended treatments for severe hypertriglyceridemia include lifestyle modifications and pharmacologic interventions with fibrates and omega-3 fatty acids.

    “Current guideline-recommended treatments for severe hypertriglyceridemia include lifestyle modifications—such as dietary changes and increased physical activity—as well as pharmacologic interventions with fibrates and omega-3 fatty acids [34, 35].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [34] Mirbolouk M, Med MBCCJ, 2020 undefined. ACC/AHA lipid guidelines: personalized care to prevent cardiovascular disease IF: NA NA NA. researchgate.netM Mirbolouk, MJ BlahaCleve Clin J Med, 2020•researchgate.net [Internet]. [cited 2025 Apr 16]; Available from: https://www.researchgate.net/profile/Cara-Reiter-Brennan/publication/340371888_ACCAHA_lipid_guidelines_Personalized_care_to_prevent_cardiovascular_disease/links/5ecbafcda6fdcc90d69753c3/ACC-AHA-lipid-guidelines-Personalized-care-to-prevent-cardiovascular-disease.pdf

      Not checked in the free run.

    • cites [35] Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J [Internet]. 2020 Jan 1 [cited 2025 Apr 16];41(1):111–88. Available from: https://dx.doi.org/10.1093/eurheartj/ehz455 source

      The ‘Defining Hypertriglyceridemia’ section defines severe hypertriglyceridemia and discusses its risks, but does not give treatment recommendations. Searches for fibrates, omega-3 fatty acids, diet, lifestyle changes, and guideline-recommended treatment found no passage supporting the attributed treatment list. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Individuals with loss-of-function mutations in APOC-III have significantly reduced triglycerides and remnant cholesterol, and a nearly 40% lower ASCVD risk.

    “Individuals with loss-of-function mutations in APOC-III exhibit significantly reduced levels of triglycerides and remnant cholesterol, along with a nearly 40% reduction in ASCVD risk [32, 33].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [32] Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease . New England Journal of Medicine [Internet]. 2014 Jul 3 [cited 2025 Apr 16];371(1):22–31. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa1307095 source

      The Results report 39% lower triglycerides and 40% lower coronary heart disease risk among carriers of the studied APOC3 variants. The paper does not report a measured reduction in remnant cholesterol, and its risk estimate is for coronary heart disease rather than ASCVD as a whole. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [33] Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease . New England Journal of Medicine [Internet]. 2014 Jul 3 [cited 2025 Apr 16];371(1):32–41. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa1308027 source

      Section 9.1.4 (page unavailable) says that ApoC-III loss-of-function mutations are associated with low triglyceride levels. The passages in our copy do not establish reduced remnant cholesterol or a nearly 40% reduction in ASCVD risk for mutation carriers. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    These findings suggest that glycemic disturbances may be transient and, if necessary, manageable with standard antihyperglycemic therapy.

    “These findings suggest that glycemic disturbances may be transient and, if necessary, manageable with standard antihyperglycemic therapy [43].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [43] Tardif JC, Investigators for the OS, Karwatowska-Prokopczuk E, Investigators for the OS, Amour ES, Investigators for the OS, et al. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J [Internet]. 2022 Apr 6 [cited 2025 Apr 16];43(14):1401–12. Available from: https://dx.doi.org/10.1093/eurheartj/ehab820 source

      The Eligibility section (p. 4) discusses restrictions on diabetes and changes to antidiabetic medication, while Patients (p. 5) reports medication use at baseline. Neither addresses whether glycemic disturbances were transient or manageable with standard therapy. Searches for glycemic changes, hyperglycemia, and antihyperglycemic treatment found no passage establishing that point. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Similar glycemic effects have previously been reported with volanesorsen and were not associated with clinically significant deterioration in glycemic control, even after long-term use up to five years.

    “However, similar effects have previously been reported with volanesorsen and were not associated with clinically significant deterioration in glycemic control, even after long-term use of up to five years [41, 42].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [41] Gouni-Berthold I, Alexander VJ, Yang Q, et al. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol [Internet]. 2021 May 1 [cited 2025 Apr 16];9(5):264–75. Available from: https://www.thelancet.com/action/showFullText?pii=S2213858721000462 source
    • cites [42] Jones A, Peers K, Wierzbicki AS, et al. Long-term effects of volanesorsen on triglycerides and pancreatitis in patients with familial chylomicronaemia syndrome (FCS) in the UK Early Access to Medicines Scheme (EAMS). Atherosclerosis. 2023 Jun 1;375:67–74. source

      The Abstract and §3.2 report volanesorsen exposure of up to 51 months, close to five years. Section 3.6 reports one newly diagnosed case of diabetes mellitus that was not assessed as treatment-related. The paper does not report the similar glycemic effects or assess whether glycemic control deteriorated over long-term use. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The meta-analysis included 1,514 participants, with 534 assigned to plozasiran and 980 receiving placebo.

    “The meta-analysis included data from 4 clinical trials [16, 17, 22, 23], encompassing a total of 1,514 participants—534 assigned to various doses and treatment durations of plozasiran, and 980 receiving placebo.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [16] Ballantyne CM, Vasas S, Azizad M, et al. Plozasiran, an RNA interference agent targeting APOC3, for mixed hyperlipidemia. N Engl J Med. 2024. https://doi.org/10.1056/NEJMoa2404143. source
    • cites [17] Watts GF, Rosenson RS, Hegele RA et al. Plozasiran for managing persistent chylomicronemia and pancreatitis risk. New Engl J Med [Internet]. 2024 Jan 9 [cited 2025 Apr 16]; Available from: https://www.nejm.org/doi/abs/https://doi.org/10.1056/NEJMoa2409368. source
    • cites [22] Gaudet D, Clifton P, Sullivan D et al. RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia. NEJM Evidence [Internet]. 2023 Nov 17 [cited 2025 Apr 16];2(12). Available from: https://evidence.nejm.org/doi/full/https://doi.org/10.1056/EVIDoa2200325. source
    • cites [23] Gaudet D, Pall D, Watts GF et al. Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial. JAMA Cardiol [Internet]. 2024 Jul 1 [cited 2025 Apr 16];9(7):620–30. Available from: https://jamanetwork.com/journals/jamacardiology/fullarticle/2817469. source

  • The quote only partly states this claim.

    Findingown data

    In subgroup analysis at the end of the study, all evaluated plozasiran dose/regimen groups showed statistically significant increases in HDL-C levels compared with placebo.

    “Subgroup analysis at the end of the study, stratified by regimen and plozasiran dose, revealed statistically significant increases in HDL-C levels compared to placebo in the following groups”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Plozasiran was associated with a higher incidence of any adverse events compared with placebo.

    “Regarding safety, patients receiving plozasiran experienced a higher incidence of any adverse events, headache, and mild rises in HbA1C levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    APOC-III analyses at 24 weeks and at the end of the study exhibited significant heterogeneity that was not resolved by the leave-one-out test.

    “Both analyses at 24 weeks (P < 0.0001, I² = 76%) and at the end of the study (P < 0.0001, I² = 82%) exhibited significant heterogeneity, which was not resolved by the leave-one-out test (Supplementary file Fig. 3A, 3B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    HDL-C analysis at 24 weeks showed significant heterogeneity (P = 0.02, I2 = 60%), which was resolved by excluding the study by Ballantyne et al. (2024) (50 mg H) (P = 0.15, I2 = 38%).

    “At 24 weeks, the analysis showed significant heterogeneity (P = 0.02, I² = 60%), which was resolved by excluding the study by Ballantyne et al. (2024) [16] (50 mg, H) (P = 0.15, I² = 38%).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Ballantyne CM, Vasas S, Azizad M, et al. Plozasiran, an RNA interference agent targeting APOC3, for mixed hyperlipidemia. N Engl J Med. 2024. https://doi.org/10.1056/NEJMoa2404143. source

  • The quote only partly states this claim.

    Findingown data

    Plozasiran was associated with a higher incidence of headache compared with placebo.

    “Regarding safety, patients receiving plozasiran experienced a higher incidence of any adverse events, headache, and mild rises in HbA1C levels.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In subgroup analysis at the end of the study, all evaluated plozasiran dose/regimen groups showed statistically significant reductions in APOC-III levels compared with placebo.

    “Subgroup analysis at the end of the study, stratified by plozasiran regimen and dose, revealed statistically significant reductions in APOC-III levels compared to placebo in the following groups”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Plozasiran was associated with mild rises in HbA1C levels compared with placebo.

    “Regarding safety, patients receiving plozasiran experienced a higher incidence of any adverse events, headache, and mild rises in HbA1C levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All included studies were found to have a low overall risk of bias, with adequate randomization, allocation concealment, and outcome measurement and analysis.

    “All studies were found to have a low overall risk of bias, with adequate randomization, allocation concealment, and outcome measurement and analysis (Supplementary file Fig. 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At the end of the study, heterogeneity was still observed for Non-HDL cholesterol (P = 0.04, I2 = 48%) and was not resolved by the leave-one-out test.

    “In contrast, heterogeneity was still observed at the end of the study (P = 0.04, I² = 48%), but was not resolved by the leave-one-out test”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Plozasiran's effect on LDL-C was minimal and did not reach statistical significance.

    “In contrast, its effect on LDL-C was minimal and did not reach statistical significance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HDL-C analysis at the end of the study showed significant heterogeneity (P < 0.00001, I2 = 77%) that was not resolved by the leave-one-out test.

    “Similarly, at the end of the study, heterogeneity remained significant (P < 0.00001, I² = 77%) but was not resolved by the leave-one-out test (Supplementary file Fig. 4A, 4B).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Plozasiran showed no statistically significant difference in serious adverse events compared to placebo at the end of the study (RR = 0.77, 95% CI [0.53, 1.13], P = 0.19).

    “Our analysis showed no statistically significant difference in the occurrence of any adverse events between the polzasiran group and placebo at the end of the study (RR = 0.77, 95% CI [0.53, 1.13], P = 0.19)”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    At 24 weeks, the Non-HDL cholesterol analysis exhibited significant heterogeneity (P = 0.02, I2 = 62%).

    “At 24 weeks, the analysis exhibited significant heterogeneity (P = 0.02, I² = 62%)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LDL-C analysis at 24 weeks exhibited significant heterogeneity (P < 0.00001, I2 = 81%) that was not resolved by the leave-one-out test.

    “At 24 weeks, the analysis exhibited significant heterogeneity (P < 0.00001, I² = 81%), which was not resolved by the leave-one-out test.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both ApoB analyses at 24 weeks and at the end of the study showed homogeneity.

    “Both analyses at 24 weeks (P = 0.30, I² = 17%) and at the end of the study (P = 0.50, I² = 0%) showed homogeneity”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Recent trials by Watts et al. (2025) and Gaudet et al. (2024) demonstrated that plozasiran achieved guideline-recommended triglyceride targets (<500 mg/dL) and reduced the incidence of acute pancreatitis events.

    “In contrast, recent trials by Watts et al. (2025) [17] and Gaudet et al. (2024) [23] demonstrated that plozasiran was able to achieve guideline-recommended triglyceride targets (< 500 mg/dL) and reduce the incidence of acute pancreatitis events [Watts 2025; Gaudet 2024].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Watts GF, Rosenson RS, Hegele RA et al. Plozasiran for managing persistent chylomicronemia and pancreatitis risk. New Engl J Med [Internet]. 2024 Jan 9 [cited 2025 Apr 16]; Available from: https://www.nejm.org/doi/abs/https://doi.org/10.1056/NEJMoa2409368. source
    • cites [23] Gaudet D, Pall D, Watts GF et al. Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial. JAMA Cardiol [Internet]. 2024 Jul 1 [cited 2025 Apr 16];9(7):620–30. Available from: https://jamanetwork.com/journals/jamacardiology/fullarticle/2817469. source

  • May combine two claims.

    Findingreasoning

    Plozasiran improves levels of non-HDL cholesterol, HDL-C, and apolipoprotein B (ApoB) beyond its triglyceride-lowering effects.

    “Beyond its triglyceride-lowering effects, plozasiran also improves levels of non–HDL cholesterol, HDL-C, and apolipoprotein B (ApoB), further supporting its role in ASCVD risk reduction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Plozasiran's inhibition of APOC-III synthesis leads to significant improvements in multiple lipid parameters, as demonstrated in RCTs and the meta-analysis.

    “As demonstrated in both RCTs and our meta-analysis, plozasiran’s inhibition of APOC-III synthesis leads to significant improvements in multiple lipid parameters.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Plozasiran demonstrated only modest effects on LDL-C, occasionally showing slight increases.

    “While reducing LDL-C is widely recognized as beneficial for improving clinical outcomes in patients with ASCVD, plozasiran demonstrated only modest effects on LDL-C—occasionally showing slight increases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Changes in ALT and AST levels were dose- and regimen-dependent and associated with higher and more frequent doses of plozasiran.

    “Subgroup analyses confirmed that changes in HbA1c, ALT, and AST levels were dose- and regimen-dependent.”
    • Also stated in: § Explanation of Findings · plain
      “Moreover, the rises seen in liver transaminases were considered non-serious and associated with higher and more frequent doses of plozasiran, which trials mitigated by changing dosing and frequency [16, 22].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Ballantyne CM, Vasas S, Azizad M, et al. Plozasiran, an RNA interference agent targeting APOC3, for mixed hyperlipidemia. N Engl J Med. 2024. https://doi.org/10.1056/NEJMoa2404143. source
    • cites [22] Gaudet D, Clifton P, Sullivan D et al. RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia. NEJM Evidence [Internet]. 2023 Nov 17 [cited 2025 Apr 16];2(12). Available from: https://evidence.nejm.org/doi/full/https://doi.org/10.1056/EVIDoa2200325. source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A systematic search was conducted in PubMed, Scopus, Web of Science, and Cochrane CENTRAL for studies published from database inception to February 19th, 2025.

    “A systematic search was conducted in PubMed, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies published from database inception to February 19th, 2025.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Two independent authors extracted the data in a standardized Excel sheet.

    “Two independent authors extracted the data in a standardized Excel sheet, including studies’ characteristics (e.g. author, date, study design), patients’ demographics, baseline characteristics as co-morbidities, Metabolic profile; baseline triglyceride level, APOC-III Level, concomitant medication use and outcomes of interest.”
    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 independent authors conducted the study screening process, with conflicts resolved by discussion and a third author's opinion.

    “Two independent authors conducted the study screening process, and the conflicts were resolved by discussion and a third author’s opinion.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Familial chylomicronemia syndrome is caused by loss-of-function mutations in the lipoprotein lipase gene, leading to triglyceride levels often exceeding 880 mg/dL.

    “Among genetic forms, familial chylomicronemia syndrome (FCS) is particularly severe, caused by loss-of-function mutations in the lipoprotein lipase (LPL) gene, leading to triglyceride levels often exceeding 880 mg/dL [5, 6].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Falko JM. Familial chylomicronemia syndrome: A clinical guide for endocrinologists. Endocr Pract. 2018;24(8):756–63. source
    • cites [6] Austin MA, McKnight B, Edwards KL, et al. Cardiovascular disease mortality in familial forms of hypertriglyceridemia: a 20-year prospective study. Circulation. 2000;101(24):2777–82. https://doi.org/10.1161/01.CIR.101.24.2777 source

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

    Study design and conductnone given

    The protocol was prospectively registered with PROSPERO under registration number CRD420251026605.

    “The protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number [CRD420251026605].”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Publication bias could not be assessed due to the limited number of included studies.

    “Publication bias could not be assessed due to the limited number of included studies in this meta-analysis.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    For LDL-C, heterogeneity assessments were not applicable for the 10 mg M, 25 mg M, 50 mg M, 50 mg H, and 100 mg M groups because these outcomes were reported in a single study.

    “heterogeneity assessments were not applicable for the 10 mg M, 25 mg M, 50 mg M, 50 mg H, and 100 mg M groups, as these outcomes were reported in a single study”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    For ApoB, homogeneity could not be assessed in the 10 mg M, 25 mg M, 50 mg M, 50 mg H, and 100 mg M groups because the outcome was reported in only one study.

    “However, homogeneity could not be assessed in the 10 mg M, 25 mg M, 50 mg M, 50 mg H, and 100 mg M groups, as the outcome was reported in only one study”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    For serious adverse events, homogeneity could not be assessed in the 10 mg M, 25 mg M, 50 mg M, 50 mg H, and 100 mg M groups because the outcome was reported in only one study.

    “However, homogeneity could not be assessed in the 10 mg M, 25 mg M, 50 mg M, 50 mg H, and 100 mg M groups, as the outcome was reported in only one study”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The 10 mg M, 25 mg M, 50 mg M, 50 mg H, and 100 mg M groups were based on single-study data.

    “The 10 mg M, 25 mg M, 50 mg M, 50 mg H, and 100 mg M groups were based on single-study data.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In hypertriglyceridemia, the liver produces VLDL particles enriched with APOC-III instead of ApoE, which impairs their clearance and promotes the formation of LDL, thereby exacerbating disease progression.

    “In hypertriglyceridemia, the liver produces VLDL particles enriched with APOC-III instead of ApoE, which impairs their clearance and promotes the formation of LDL, thereby exacerbating disease progression [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Sacks FM. The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia. Curr Opin Lipidol [Internet]. 2015 Feb 13 [cited 2025 Apr 16];26(1):56–63. Available from: https://journals.lww.com/co-lipidology/fulltext/2015/02000/the_crucial_roles_of_apolipoproteins_e_and_c_iii.10.aspx. source

  • May combine two claims.

    Interpretationreasoning

    These findings support plozasiran's potential utility across a range of dyslipidemic disorders and suggest a role in reducing the risk of acute pancreatitis and ASCVD, particularly in patients with hypertriglyceridemia and mixed dyslipidemia.

    “These findings support its potential utility across a range of dyslipidemic disorders and suggest a role in reducing the risk of conditions such as acute pancreatitis and ASCVD, particularly in patients with hypertriglyceridemia and mixed dyslipidemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The meta-analysis addressed heterogeneity by analyzing outcomes at the 24-week mark and conducting subgroup analyses based on dose and regimen.

    “Although we addressed this by analyzing outcomes at the 24-week mark and conducting subgroup analyses based on dose and regimen”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Watts et al. (2025) focused on individuals with genetically confirmed familial chylomicronemia syndrome (FCS) or symptomatic persistent chylomicronemia, aiming to assess reductions in acute pancreatitis events.

    “Watts et al. (2025) focused on individuals with genetically confirmed familial chylomicronemia syndrome (FCS) or symptomatic persistent chylomicronemia, aiming to assess reductions in acute pancreatitis events [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Watts GF, Rosenson RS, Hegele RA et al. Plozasiran for managing persistent chylomicronemia and pancreatitis risk. New Engl J Med [Internet]. 2024 Jan 9 [cited 2025 Apr 16]; Available from: https://www.nejm.org/doi/abs/https://doi.org/10.1056/NEJMoa2409368. source

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

    Premisecitation

    Ballantyne et al. (2024) included patients with mixed dyslipidemia to explore whether plozasiran's lipid-lowering effects could extend to individuals at risk for ASCVD and support the rationale for a dedicated cardiovascular outcomes trial.

    “Ballantyne et al. (2024) included patients with mixed dyslipidemia to explore whether plozasiran’s lipid-lowering effects could extend to individuals at risk for ASCVD and support the rationale for a dedicated cardiovascular outcomes trial [16].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Ballantyne CM, Vasas S, Azizad M, et al. Plozasiran, an RNA interference agent targeting APOC3, for mixed hyperlipidemia. N Engl J Med. 2024. https://doi.org/10.1056/NEJMoa2404143. source
47 of 47

  • The paper relies on this without support.

    APOC-III significantly influences lipoprotein metabolism through both LPL-dependent and LPL-independent mechanisms.

    “It significantly influences lipoprotein metabolism through both lipoprotein lipase (LPL)–dependent and LPL-independent mechanisms.”

  • The paper relies on this without support.

    The efficacy and safety of plozasiran had not been comprehensively evaluated through a systematic review or meta-analysis before this study.

    “Despite its promising therapeutic potential [16, 17], the efficacy and safety of plozasiran have not yet been comprehensively evaluated through a systematic review or meta-analysis.”

  • The paper relies on this without support.

    Plozasiran is a siRNA that specifically targets and degrades mRNA encoding APOC-III.

    “Plozasiran is a siRNA that specifically targets and degrades mRNA encoding APOC-III.”

  • The paper relies on this without support.

    APOC-III is a glycoprotein synthesized in hepatocytes and found in several lipoproteins, including chylomicrons, VLDL, LDL, and HDL.

    “APOC-III is a glycoprotein synthesized in hepatocytes and found in several lipoproteins, including chylomicrons (CMs), VLDL, LDL, and HDL.”

  • The paper relies on this without support.

    APOC-III exerts a significant influence on lipoprotein metabolism through both LPL-dependent and LPL-independent mechanisms.

    “It exerts a significant influence on lipoprotein metabolism through both lipoprotein lipase (LPL)–dependent and LPL-independent mechanisms.”

  • The paper relies on this without support.

    APOC-III inhibits LPL activity and disrupts ApoE-mediated hepatic clearance of CMs and VLDL remnants, leading to elevated levels of TRLs.

    “Notably, APOC-III inhibits LPL activity and disrupts ApoE-mediated hepatic clearance of CMs and VLDL remnants, leading to elevated levels of TRLs.”

  • The paper relies on this without support.

    This is the first meta-analysis to focus exclusively on plozasiran.

    “To our knowledge, this is the first meta-analysis to focus exclusively on plozasiran, the most recently investigated APOC-III inhibitor.”

  • The paper relies on this without support.

    Individual studies may be underpowered to detect statistically significant effects across all outcomes or subgroups.

    “Unlike individual studies, which may be underpowered to detect statistically significant effects across all outcomes or subgroups, our pooled analysis enables more precise effect estimates, clarifies consistency across different dosing regimens, and reveals dose-dependent patterns in both efficacy and adverse effects.”

  • The paper relies on this without support.

    Improvements in the measured lipid parameters (TG, APOC-III, HDL-C, non-HDL-C, ApoB) translate into clinical benefit for patients with dyslipidemic disorders.

    “our findings suggest that plozasiran may help reduce ASCVD risk”
    “While Plozasiran shows strong potential as a therapeutic option for severe dyslipidemic conditions”
9 of 9

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.

  • Discussion denies the reported significant ALT increase

    Major

    The discussion says plozasiran did not meaningfully affect ALT at either time point, but the results report a statistically significant ALT increase at both.

  • ApoB 10 mg monthly confidence interval is not centered on its estimate

    Minor

    The midpoint of the reported 95% confidence interval is −15.74, not the reported mean difference of −13.90. The printed interval also excludes zero despite the accompanying nonsignificant P = 0.08.

    Reported -13.9 · recomputed -15.74

  • Serious-adverse-event result is labeled as any adverse events

    Minor

    The serious-adverse-events section calls its nonsignificant result a result for any adverse events, contradicting the separately reported significant increase in any adverse events.

  • Abstract calls HDL-C increases reductions

    Minor

    The abstract says quarterly dosing reduced HDL-C, whereas the efficacy results report significant HDL-C increases for those regimens.

  • Baseline APOC-III range mixes units

    Minor

    The stated lower endpoint of 14.6 is reported in the table in mg/liter, not mg/dL. It therefore cannot be the 14.6 mg/dL lower endpoint stated in the text.

  • Half-yearly arm has the quarterly dosing schedule

    Minor

    Table 1 labels the 50 mg arm half-yearly but gives it doses on Day 1 and week 12-the same schedule it gives the 50 mg quarterly arm.

  • LDL-C 50 mg monthly confidence interval is not centered on its estimate

    Minor

    The reported confidence interval has a midpoint of 37.00, rather than the reported mean difference of 59.50.

    Reported 59.5 · recomputed 37

7 of 7

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J [Internet]. 2020 Jan 1 [cited 2025 Apr 16];41(1):111–88. Available from: https://dx.doi.org/10.1093/eurheartj/ehz455 · DOI · Paper page

Cited by

Sorted by citations

Authors
Sydhom, P., Al-Quraishi, B., Gohar, A., El-Shawaf, M., Shehata, N., Ataya, M., Sydhom, M., Awwad, N., Motawade, H., Naji, N., & Abdelgalil, M. S.
Affiliations
Ain Shams University (EG)
Corresponding author
  • Sydhom, Pishoy
  • Al-Quraishi, Bakr
  • Gohar, Aya
  • El-Shawaf, Mohamad
  • Shehata, Nahla
  • Ataya, Miral
  • Sydhom, Mark
  • Awwad, Nouran
  • Motawade, Haidy
  • Naji, Nourhan
  • Abdelgalil, Mahmoud Shaaban
ORCID
Venue
Cardiovascular Drugs and Therapy
Publisher
Springer Science and Business Media LLC
Published
2025-11-18
Volume
40
Issue
3
Pages
1085-1106
ISSN
  • 0920-3206 (ISSN-L)
  • 1573-7241
DOI
10.1007/s10557-025-07798-8
PMC
PMC13171978
OpenAlex
W4416307154
Cited by
5
References
41
Citations by year
2026: 5
FWCI
1.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Cardiovascular Drugs and Therapy (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
Ain Shams University
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
plozasiran, apolipoprotein C-III, dyslipidemia, triglycerides, non-HDL cholesterol, HDL cholesterol, apolipoprotein B, RNA interference therapy, lipid-lowering therapy, dose-dependent effects, adverse events, HbA1c
MeSH terms
Hypolipidemic Agents, Humans, Lipids, Triglycerides, Biomarkers, Treatment Outcome, Dyslipidemias, Apolipoprotein C-III

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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