Efficacy and Safety of Apolipoprotein C‐ III Inhibitors in Hypertriglyceridemia: A Network Meta‐Analysis of Randomised Controlled Trials
Abstract
Background: Hypertriglyceridemia is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). We aimed to evaluate the efficacy and safety of apolipoprotein C‐III (ApoC‐III) inhibitors in patients with hypertriglyceridemia. Methods: Electronic databases were systematically searched for randomised controlled trials (RCTs) comparing ApoC‐III inhibitors (Volanesorsen, Olezarsen and Plozasiran) with placebo. A frequentist network meta‐analysis was performed. Continuous outcomes were presented as mean differences (MDs), and dichotomous outcomes as risk ratios (RRs), both with 95% confidence intervals (CIs). Results: A total of 15 RCTs involving 3934 patients were included. All ApoC‐III inhibitors demonstrated significant reductions in TG, except for Volanesorsen 100 mg Q1W and Olezarsen 10 mg Q4W. Olezarsen 80 mg administered every 4 weeks had the highest SUCRA ranking for TG reduction (MD: −63.26; 95% CI: −70.04 to −56.47; p < 0.01). Moreover, ApoC‐III inhibitors were associated with a significant reduction in the incidence of pancreatitis (HR: 0.16, 95% CI: 0.07–0.33, p < 0.01). None of the agents significantly increased the risk of serious adverse events. Conclusions: ApoC‐III inhibitors significantly improved triglyceride levels and other lipid parameters and, most importantly, substantially reduced the risk of acute pancreatitis. Future trials are needed to evaluate their effects on cardiovascular outcomes.
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The PRISMA 2020 statement: An updated guideline for reporting systematic reviews
Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., Shamseer, L., Tetzlaff, J. M., Akl, E. A., Brennan, S. E., et al. (2021) · BMJ · doi:10.1136/bmj.n71 · Cited by 108,283 · see citing works
Measuring inconsistency in meta-analyses
Higgins, J. P. T., Thompson, S. G., Deeks, J. J., & Altman, D. G. (2003) · BMJ · doi:10.1136/bmj.327.7414.557 · Cited by 63,139 · see citing works
Bias in meta-analysis detected by a simple, graphical test
Egger, M., Smith, G. D., Schneider, M., & Minder, C. (1997) · BMJ · doi:10.1136/bmj.315.7109.629 · Cited by 56,722 · see citing works
Rayyan-a web and mobile app for systematic reviews.
Ouzzani, M., Hammady, H., Fedorowicz, Z., & Elmagarmid, A. (2016) · Systematic Reviews · doi:10.1186/s13643-016-0384-4 · Cited by 26,092 · see citing works
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz455 · Cited by 8,961 · see citing works
Cumpston, M., Li, T., Page, M. J., Chandler, J., Welch, V. A., Higgins, J. P., & Thomas, J. (2019) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.ed000142 · Cited by 7,218 · see citing works
Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes
Cannon, C. P., Braunwald, E., McCabe, C. H., Rader, D. J., Rouleau, J. L., Belder, R., Joyal, S. V., Hill, K. A., Pfeffer, M. A., & Skene, A. M. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040583 · Cited by 4,938 · see citing works
Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia
Bhatt, D. L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Doyle, R. T., Juliano, R. A., Jiao, L., Granowitz, C., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1812792 · Cited by 3,317 · see citing works
Grundy, S. M., Stone, N. J., Bailey, A. L., Beam, C., Birtcher, K. K., Blumenthal, R. S., Braun, L. T., de Ferranti, S., Faiella-Tommasino, J., Forman, D. E., et al. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.11.003 · Cited by 2,691 · see citing works
Remnant Cholesterol as a Causal Risk Factor for Ischemic Heart Disease
Varbo, A., Benn, M., Tybjærg-Hansen, A., Jørgensen, A. B., Frikke-Schmidt, R., & Nordestgaard, B. G. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.08.1026 · Cited by 1,115 · see citing works
Common variants associated with plasma triglycerides and risk for coronary artery disease
Do, R., Willer, C. J., Schmidt, E. M., Sengupta, S., Gao, C., Peloso, G. M., Gustafsson, S., Kanoni, S., Ganna, A., Chen, J., et al. (2013) · Nature Genetics · doi:10.1038/ng.2795 · Cited by 862 · see citing works
Ference, B. A., Kastelein, J. J. P., Ray, K. K., Ginsberg, H. N., Chapman, M. J., Packard, C. J., Laufs, U., Oliver-Williams, C., Wood, A. M., Butterworth, A. S., et al. (2019) · JAMA · doi:10.1001/jama.2018.20045 · Cited by 724 · cited 1× · see citing works
“Mendelian randomisation studies demonstrate that genetic variants associated with lifelong lower TG and remnant cholesterol levels are linked to a correspondingly lower risk of coronary artery disease, independent of LDL-C [56, 57].”
Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome
Witztum, J. L., Gaudet, D., Freedman, S. D., Alexander, V. J., Digenio, A., Williams, K. R., Yang, Q., Hughes, S. G., Geary, R. S., Arca, M., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1715944 · Cited by 669 · see citing works
Hypertriglyceridemia: its etiology, effects and treatment
Yuan, G., Al-Shali, K. Z., & Hegele, R. A. (2007) · Canadian Medical Association Journal · doi:10.1503/cmaj.060963 · Cited by 624 · see citing works
Clinical review on triglycerides
Laufs, U., Parhofer, K. G., Ginsberg, H. N., & Hegele, R. A. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz785 · Cited by 544 · see citing works
<b>netmeta</b> : An <i>R</i> Package for Network Meta-Analysis Using Frequentist Methods
Balduzzi, S., Rücker, G., Nikolakopoulou, A., Papakonstantinou, T., Salanti, G., Efthimiou, O., & Schwarzer, G. (2023) · Journal of Statistical Software · doi:10.18637/jss.v106.i02 · Cited by 532 · see citing works
Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia
Gaudet, D., Alexander, V. J., Baker, B. F., Brisson, D., Tremblay, K., Singleton, W., Geary, R. S., Hughes, S. G., Viney, N. J., Graham, M. J., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1400283 · Cited by 528 · see citing works
Virani, S. S., Morris, P. B., Agarwala, A., Ballantyne, C. M., Birtcher, K. K., Kris-Etherton, P. M., Ladden-Stirling, A. B., Miller, M., Orringer, C. E., & Stone, N. J. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.06.011 · Cited by 341 · see citing works
Reconstructing Time-to-event Data from Published Kaplan–Meier Curves
Wei, Y., & Royston, P. J. (2017) · The Stata Journal Promoting communications on statistics and Stata · doi:10.1177/1536867x1801700402 · Cited by 283 · see citing works
Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome
Stroes, E. S. G., Alexander, V. J., Karwatowska-Prokopczuk, E., Hegele, R. A., Arca, M., Ballantyne, C. M., Soran, H., Prohaska, T. A., Xia, S., Ginsberg, H. N., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2400201 · Cited by 271 · see citing works
Using Risk of Bias 2 to assess results from randomised controlled trials: guidance from Cochrane
Flemyng, E., Moore, T. H., Boutron, I., Higgins, J. P., Hróbjartsson, A., Nejstgaard, C. H., & Dwan, K. (2023) · BMJ Evidence-Based Medicine · doi:10.1136/bmjebm-2022-112102 · Cited by 264 · see citing works
Gouni-Berthold, I., Alexander, V. J., Yang, Q., Hurh, E., Steinhagen-Thiessen, E., Moriarty, P. M., Hughes, S. G., Gaudet, D., Hegele, R. A., O'Dea, L. S. L., et al. (2021) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(21)00046-2 · Cited by 232 · see citing works
Management of hypertriglyceridemia
Simha, V. (2020) · BMJ · doi:10.1136/bmj.m3109 · Cited by 227 · see citing works
Tardif, J.-C., Karwatowska-Prokopczuk, E., Amour, E. S., Ballantyne, C. M., Shapiro, M. D., Moriarty, P. M., Baum, S. J., Hurh, E., Bartlett, V. J., Kingsbury, J., et al. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehab820 · Cited by 210 · see citing works
Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia
Ballantyne, C. M., Vasas, S., Azizad, M., Clifton, P., Rosenson, R. S., Chang, T., Melquist, S., Zhou, R., Mushin, M., Leeper, N. J., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2404143 · Cited by 210 · see citing works
Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk
Bergmark, B. A., Marston, N. A., Prohaska, T. A., Alexander, V. J., Zimerman, A., Moura, F. A., Murphy, S. A., Goodrich, E. L., Zhang, S., Gaudet, D., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2402309 · Cited by 198 · see citing works
Klempfner, R., Erez, A., Sagit, B.-Z., Goldenberg, I., Fisman, E., Kopel, E., Shlomo, N., Israel, A., & Tenenbaum, A. (2016) · Circulation: Cardiovascular Quality and Outcomes · doi:10.1161/circoutcomes.115.002104 · Cited by 180 · see citing works
Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk
Watts, G. F., Rosenson, R. S., Hegele, R. A., Goldberg, I. J., Gallo, A., Mertens, A., Baass, A., Zhou, R., Muhsin, M., Hellawell, J., et al. (2025) · New England Journal of Medicine · doi:10.1056/nejmoa2409368 · Cited by 178 · cited 1× · see citing works
“Only 3 studies reported the incidence of pancreatitis [7, 42, 44].”
Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia
Gaudet, D., Pall, D., Watts, G. F., Nicholls, S. J., Rosenson, R. S., Modesto, K., San Martin, J., Hellawell, J., & Ballantyne, C. M. (2024) · JAMA Cardiology · doi:10.1001/jamacardio.2024.0959 · Cited by 172 · cited 2× · see citing works
“The effects of these inhibitors on the broader atherogenic lipid profile—particularly on low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB)—are inconsistent across trials [17–20].”
Digenio, A., Dunbar, R. L., Alexander, V. J., Hompesch, M., Morrow, L., Lee, R. G., Graham, M. J., Hughes, S. G., Yu, R., Singleton, W., et al. (2016) · Diabetes Care · doi:10.2337/dc16-0126 · Cited by 170 · see citing works
Apolipoprotein C-III in triglyceride-rich lipoprotein metabolism
Ramms, B., & Gordts, P. L. S. M. (2018) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000502 · Cited by 103 · see citing works
Daly, C., Neupane, B., Beyene, J., Thabane, L., Straus, S. E., & Hamid, J. S. (2019) · BMJ Open · doi:10.1136/bmjopen-2018-024625 · Cited by 90 · see citing works
Targeting <i>APOC3</i> with Olezarsen in Moderate Hypertriglyceridemia
Bergmark, B. A., Marston, N. A., Prohaska, T. A., Alexander, V. J., Zimerman, A., Moura, F. A., Kang, Y. M., Weinland, J., Murphy, S. A., Goodrich, E. L., et al. (2025) · New England Journal of Medicine · doi:10.1056/nejmoa2507227 · Cited by 78 · see citing works
Oral, E. A., Garg, A., Tami, J. A., Huang, E. A., O'Dea, L. S. L., Schmidt, H., Tiulpakov, A. N., Mertens, A. C., Alexander, V. J., Watts, L. M., et al. (2022) · Journal of clinical lipidology · doi:10.1016/j.jacl.2022.08.008 · Cited by 75 · see citing works
RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia
Gaudet, D., Clifton, P., Sullivan, D., Baker, J., Schwabe, C., Thackwray, S., Scott, R., Hamilton, J., Given, B., Melquist, S., et al. (2023) · NEJM Evidence · doi:10.1056/evidoa2200325 · Cited by 71 · see citing works
New Therapies for Lowering Triglyceride-Rich Lipoproteins
Rosenson, R. S., Shaik, A., & Song, W. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.08.051 · Cited by 67 · see citing works
Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk
Marston, N. A., Bergmark, B. A., Alexander, V. J., Prohaska, T. A., Kang, Y. M., Moura, F. A., Zimerman, A., Waldman, E., Weinland, J., Murphy, S. A., et al. (2026) · New England Journal of Medicine · doi:10.1056/nejmoa2512761 · Cited by 62 · see citing works
Remnant cholesterol and ischemic heart disease
Varbo, A., & Nordestgaard, B. G. (2014) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000093 · Cited by 56 · see citing works
Karwatowska‐Prokopczuk, E., Tardif, J., Gaudet, D., Ballantyne, C. M., Shapiro, M. D., Moriarty, P. M., Baum, S. J., Amour, E. S., Alexander, V. J., Xia, S., et al. (2022) · Journal of clinical lipidology · doi:10.1016/j.jacl.2022.06.005 · Cited by 51 · see citing works
The role of antisense oligonucleotide therapy against apolipoprotein-CIII in hypertriglyceridemia
Gouni‐Berthold, I. (2017) · Atherosclerosis Supplements · doi:10.1016/j.atherosclerosissup.2017.05.003 · Cited by 39 · see citing works
D’Erasmo, L., Gallo, A., Costanzo, A. D., Bruckert, É., & Arca, M. (2020) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2020.1787380 · Cited by 24 · see citing works
Kamrul-Hasan, A. B. M., Dutta, D., Nagendra, L., Mondal, S., Bhattacharya, S., & Kalra, S. (2024) · Endocrine Practice · doi:10.1016/j.eprac.2024.08.013 · Cited by 17 · see citing works
Mahmoud, A., Abdelsayed, K., Mohamed, A. A., Najah, Q., Abdulkader, A., Ali, K., Tabassum, S., Abouzid, M. R., Abdelazeem, B., & Mills, J. D. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-024-02389-2 · Cited by 17 · see citing works
Anti-apoC-III Therapies and Implications for Treatment of Pancreatitis and Cardiovascular Disease
Tsimikas, S. (2025) · Current Atherosclerosis Reports · doi:10.1007/s11883-025-01345-4 · Cited by 16 · see citing works
Lee, S. J., Mahankali, M., Bitar, A., Zou, H., Chao, E., Nguyen, H., González, J., Caballero, D., Hull, M. V., Wang, D., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-05163-w · Cited by 14 · see citing works
Maidman, S. D., Hegele, R. A., & Rosenson, R. S. (2024) · Current Atherosclerosis Reports · doi:10.1007/s11883-024-01258-8 · Cited by 11 · see citing works
Kraaijenhof, J. M., Peletier, M. C., Nurmohamed, N. S., Hovingh, G. K., Alexander, V. J., Tsimikas, S., Stroes, E. S. G., & Kroon, J. (2025) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwaf478 · Cited by 10 · see citing works
ApoC-III as Therapeutic Target: Is it Primetime for Clinical Use?
Biolo, M., Galimberti, F., Portinari, C., Bertocco, S., Tosin, P., Casula, M., Previato, L., Zambon, S., Simioni, P., & Zambon, A. (2025) · Current Atherosclerosis Reports · doi:10.1007/s11883-025-01315-w · Cited by 9 · see citing works
Li, J., Sun, H., Wang, Y., Liu, J., & Wang, G. (2023) · Lipids in Health and Disease · doi:10.1186/s12944-023-01797-0 · Cited by 9 · see citing works
Cheng, Y., Li, T., Tan, P., Du, Y., Huang, Z., Shi, H., Cai, T., Chen, Y., & Fu, W. (2022) · Endocrine · doi:10.1007/s12020-022-03025-8 · Cited by 9 · see citing works
Yang, X., Alexander, V. J., Xia, S., & Tsimikas, S. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2025.120462 · Cited by 7 · see citing works
Ashraf, T., Devi, N., Aradhna, F., Devi, S., Nancy, F., Kumar, A., Ameer, F., Absar, F., Kumar, L., Kumar, S., et al. (2025) · Annals of Medicine & Surgery · doi:10.1097/ms9.0000000000003505 · Cited by 6 · see citing works
Sydhom, P., Al-Quraishi, B., Gohar, A., El-Shawaf, M., Shehata, N., Ataya, M., Sydhom, M., Awwad, N., Motawade, H., Naji, N., et al. (2026) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-025-07798-8 · Cited by 5 · see citing works
Elbahloul, M. A., Elgadi, A. T., Fayed, H., Ramadan, M., Kasser, M. E., Hussein, A., Amine, H., & Labieb, F. (2025) · Annals of Medicine and Surgery · doi:10.1097/ms9.0000000000003264 · Cited by 3 · see citing works
Self-citationJoubert, S., Ninan, J., Rosario, N., Davis, S. R., Wollen, J. T., & Wang, E. M. (2025) · American Journal of Cardiovascular Drugs · doi:10.1007/s40256-025-00774-5 · Cited by 3 · see citing works
Yoo, J. H. (2025) · Cardiovascular Prevention and Pharmacotherapy · doi:10.36011/cpp.2025.7.e19 · Cited by 1 · see citing works
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- 10.18637/JSS.V106.I02 · DOI · Paper page
- 10.1186/S12874‐021‐01308‐8/FIGURES/12 · DOI
- 10.1007/S11883‐023‐01140‐Z/TABLES/2 · DOI
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- Authors
- Elbahloul, M. A., Gamal, A., Maihoub, O., Elbaz Hassan, M. M., Attia, M. K., Salah, A. M., Elboraay, T., Awad, A. K., Akoum, A., Elazab, A., & Elgendy, I. Y.
- Affiliations
- Kafrelsheikh University (EG)
- Deraya University
- Department of Pathology National Hospital Latakia Syria
- Faculty of Medicine Al‐Azhar University Cairo Egypt
- Fayoum University (EG)
- Zagazig University (EG)
- Galala University
- Hennepin County Medical Center (US)
- South Valley University (EG)
- University of Kentucky (US)
- Corresponding author
- Elbahloul, Mohammed A.
- ORCID
- Venue
- Diabetes, Obesity and Metabolism
- Publisher
- Wiley
- Published
- 2026-03-31
- Volume
- 28
- Issue
- 6
- Pages
- 5149-5162
- ISSN
- 1462-8902 (ISSN-L)
- 1463-1326
- OpenAlex
- W7147509393
- Semantic Scholar
- 8a681d51d61765b8c3a62d34376085dd55f0b729
- Cited by
- 1
- References
- 56
- Citations by year
- 2026: 1
- FWCI
- 6.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Diabetes Obesity and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- 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
- hypertriglyceridemia, volanesorsen, olezarsen, plozasiran, triglyceride lowering, pancreatitis, atherosclerotic cardiovascular disease, lipid-lowering therapy, drug safety
- MeSH terms
- Network Meta-Analysis as Topic, Hypolipidemic Agents, Humans, Indoles, Oligonucleotides, Pancreatitis, Triglycerides, Hypertriglyceridemia, Randomized Controlled Trials as Topic, Treatment Outcome, Atherosclerosis, Apolipoprotein C-III
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