Inflammation and cardiovascular disease - Part II: Anti-inflammatory therapy in cardiovascular disease

Abstract

Inflammation plays a central role in the pathogenesis of atherosclerotic cardiovascular diseases (ASCVDs), contributing to plaque progression, instability, and thrombosis. Chronic systemic inflammation exacerbates endothelial dysfunction, promotes oxidative stress, and accelerates atherogenesis, necessitating targeted interventions. This review explores established and emerging strategies for modulating inflammation to improve cardiovascular outcomes. Statin therapy remains foundational, with trials, such as JUPITER, demonstrating significant reductions in cardiovascular events through high-sensitivity C-reactive protein modulation, independent of low-density lipoprotein lowering. Non-statin lipid-lowering therapies, including proprotein convertase subtilisin/kexin type 9 inhibitors, ezetimibe, and bempedoic acid, have shown additional anti-inflammatory benefits and further reduce inflammation-driven cardiovascular risk. In addition, triglyceride-lowering agents targeting apolipoprotein C-III and angiopoietin-like protein pathways offer promising avenues for reducing metabolic inflammation and residual ASCVD risk. Anti-inflammatory pharmacotherapy has gained traction, with trials such as canakinumab anti-inflammatory thrombosis outcomes study, colchicine cardiovascular outcomes trial, and low-dose colchicine underscoring the efficacy of canakinumab and colchicine in reducing cardiovascular events. Emerging interleukin (IL) pathways (e.g., IL-17, IL-33, and IL-36) and novel therapeutic targets (e.g., cluster of differentiation 47 inhibitors, serum/glucocorticoid-regulated kinase 1 modulation, and P-selectin blockade) present future opportunities for precision cardiovascular medicine. However, residual inflammatory risk persists despite optimal lipid control, highlighting the need for a multimodal approach integrating lipid-lowering, anti-inflammatory, and targeted immunomodulatory therapies. The expanding role of inflammation in ASCVD suggests a paradigm shift toward inflammation-guided treatment strategies. Further research is warranted to refine patient selection, personalize therapy, and optimize long-term outcomes for inflammation-driven cardiovascular disease.

Keywords

Cardiovascular inflammation / Cardiovascular disease / Chronic kidney disease / Inflammation-targeted therapies / Lipid-lowering therapy / PCSK9 inhibitors and inflammation reduction / ApoC-III and triglyceride-lowering therapies

Funding

None.

Conflict of interest

Krishnaswami Vijayraghavan is the Guest Editor of this special issue but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper. Corina Grancorvitz is an employee of Kiniksa Pharmaceuticals but declared no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

References

[1] Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013; 2013(1): CD004816. doi: 10.1002/14651858.CD004816.pub5

[2] Kapur NK, Musunuru K. Clinical efficacy and safety of statins in managing cardiovascular risk. Vasc Health Risk Manag. 2008; 4(2):341-353. doi: 10.2147/vhrm.s1653

[3] Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359(21):2195-2207. doi: 10.1056/NEJMoa0807646

[4] Luo Y, Hou Y, Zhao W, Yang B. Recent progress in gene therapy for familial hypercholesterolemia treatment. iScience. 2024; 27(9):110641. doi: 10.1016/j.isci.2024.110641

[5] Pontremoli R, Bellizzi V, Bianchi S, et al. Management of dyslipidaemia in patients with chronic kidney disease: A position paper endorsed by the Italian society of nephrology. J Nephrol. 2020; 33(3):417-430. doi: 10.1007/s40620-020-00707-2

[6] Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015; 372(25):2387-2397. doi: 10.1056/NEJMoa1410489

[7] Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372(16):1489-1499. doi: 10.1056/NEJMoa1501031

[8] Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372:1500-1509. doi: 10.1056/NEJMoa1500858

[9] Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023; 388(15):1353-1364. doi: 10.1056/NEJMoa2215024

[10] Ridker PM. Effects of Effects of bempedoic acid on CRP, IL-6, fibrinogen and lipoprotein(a) in patients with residual inflammatory risk: a secondary analysis of the CLEAR Harmony trial. J Clin Lipidol. 2023; 17(3):297-304. doi: 10.1016/j.jacl.2023.02.002

[11] Malick WA, Waksman O, Do R, et al.Clinical trial design for triglyceride-rich lipoprotein-lowering therapies: JACC focus seminar 3/3. J Am Coll Cardiol. 2023; 81(16):1646-1658. doi: 10.1016/j.jacc.2023.02.034

[12] Ramms B, Patel S, Sun X, et al. Interventional hepatic apoC III knockdown improves atherosclerotic plaque stability and remodeling by triglyceride lowering. JCI Insight. 2022; 7(13):e158414. doi: 10.1172/jci.insight.158414

[13] Saklayen MG. The global epidemic of the metabolic syndrome. Curr Hypertens Rep. 2018; 20(2):12. doi: 10.1007/s11906-018-0812-z

[14] Gariani K, Jornayvaz FR. Pathophysiology of NASH in endocrine diseases. Endocr Connect. 2021; 10(2):R52-R65. doi: 10.1530/EC-20-0490

[15] Wolska A, Yang ZH, Remaley AT. Hypertriglyceridemia: New approaches in management and treatment. Curr Opin Lipidol. 2020; 31(6):331-339. doi: 10.1097/MOL.0000000000000710

[16] Jomard A, Osto E. High density lipoproteins: Metabolism, function, and therapeutic potential. Front Cardiovasc Med. 2020; 7:39. doi: 10.3389/fcvm.2020.00039

[17] Navab M, Anantharamaiah GM, Fogelman AM. The role of high-density lipoprotein in inflammation. Trends Cardiovasc Med. 2005; 15(4):158-161. doi: 10.1016/j.tcm.2005.05.008

[18] Woudberg NJ, Pedretti S, Lecour S, et al. Pharmacological intervention to modulate HDL: What do we target? Front Pharmacol. 2018; 8:989. doi: 10.3389/fphar.2017.00989

[19] Kastelein JJP, Hsieh A, Dicklin MR, Ditmarsch M, Davidson MH. Obicetrapib: Reversing the tide of CETP inhibitor disappointments. Curr Atheroscler Rep. 2024; 26(2):35-44. doi: 10.1007/s11883-023-01184-1

[20] New Amsterdam Pharma. Obicetrapib (TA-8995): A selective CETP inhibitor for lowering LDL-C. New Amsterdam Pharma. 2025. Available from: https://www.newamsterdampharma.com/obicetrapibta8995/ [Last accessed on 2025 Jan 10].

[21] Crupi R, Cuzzocrea S. Role of EPA in inflammation: Mechanisms, effects, and clinical relevance. Biomolecules. 2022; 12(2):242. doi: 10.3390/biom12020242

[22] Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019; 380(8):752-762. doi: 10.1056/NEJMoa1809798

[23] Tardif JC, Kouz S, Waters D, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019; 381(26):2497-2505. doi: 10.1056/NEJMoa1912388

[24] Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017; 377(12):1119-1131. doi: 10.1056/NEJMoa1707914

[25] Perkovic V, Tuttle K, Sattar N, et al. Design of the ZEUS trial: Interleukin-6 inhibition with ziltivekimab for cardiovascular protection in chronic kidney disease. Kidney Int Rep. 2025; 10(S1):S767. doi: 10.1016/j.ekir.2024.11.1354

[26] Ridker PM, Howard CP, Walter V, et al. Effects of interleukin-1β inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: A phase IIb randomized, placebo-controlled trial. JAMA. 2012; 307(21): 2300-2309. doi: 10.1001/jama.2012.5733

[27] O’Donoghue ML, Glaser R, Cavender MA, et al. Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: A randomized clinical trial. JAMA. 2016; 315(10):1027-1036. doi: 10.1001/jama.2016.1036

[28] Vosshenrich CAJ, Di Santo JP. Interleukin signaling. Curr Biol. 2002;12(22):R760-R763. doi: 10.1016/S0960-9822(02)01286-1

[29] Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: From bench to clinic. Signal Transduct Target Ther. 2021; 6:402. doi: 10.1038/s41392-021-00791-1

[30] Holtmann H, Enninga J, Kälble S, et al. The MAPK kinase kinase TAK1 plays a central role in coupling the interleukin-1 receptor to both transcriptional and RNA-targeted mechanisms of gene regulation. J Biol Chem. 2001;276(5): 3508-3516. doi: 10.1074/jbc.M004376200

[31] Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017; 2:e17023. doi: 10.1038/sigtrans.2017.23

[32] Chang SH, Dong C. IL-17F: Regulation, signaling and function in inflammation. Cytokine. 2009; 46(1):7-11. doi: 10.1016/j.cyto.2008.12.024

[33] Miller AM. Role of IL-33 in inflammation and disease. J Inflamm (Lond). 2011; 8(22):22. doi: 10.1186/1476-9255-8-22

[34] Lelios I, Cansever D, Utz SG, Mildenberger W, Stifter SA, Greter M. Emerging roles of IL-34 in health and disease. J Exp Med. 2020; 217(11):e20190290. doi: 10.1084/jem.20190290

[35] Yuan ZC, Xu WD, Liu XY, Liu XY, Huang AF, Su LC. Biology of IL-36 signaling and its role in systemic inflammatory diseases. Front Immunol. 2019; 10:2532. doi: 10.3389/fimmu.2019.02532

[36] Broch K, Anstensrud AK, Woxholt S, et al. Randomized trial of interleukin-6 receptor inhibition in patients with acute ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2021; 77(15):1845-1855. doi: 10.1016/j.jacc.2021.02.049

[37] Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med. 2014; 371(4):326-338. doi: 10.1056/NEJMoa1314258

[38] Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371(9625): 1665-1674. doi: 10.1016/S0140-6736(08)60725-4

[39] Gordon KB, Foley P, Krueger JG, et al. Bimekizumab efficacy and safety in moderate to severe plaque psoriasis (BE READY): A multicentre, double-blind, placebo-controlled, randomised withdrawal phase 3 trial. Lancet. 2021; 397(10275):475-486. doi: 10.1016/S0140-6736(21)00126-4

[40] Bachelez H, Choon SE, Marrakchi S, et al. Trial of spesolimab for generalized pustular psoriasis. N Engl J Med. 2021; 385(26):2431-2440. doi: 10.1056/NEJMoa2111563

[41] Kelsen SG, Agache IO, Soong W, et al. Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial. J Allergy Clin Immunol. 2021; 148(3):790-798. doi: 10.1016/j.jaci.2021.03.044

[42] Dou M, Chen Y, Hu J, Ma D, Xing Y. Recent advancements in CD47 signal transduction pathways involved in vascular diseases. Biomed Res Int. 2020; 2020:4749135. doi: 10.1155/2020/4749135

[43] Yarmohammadi F, Karimi G. The role of SGK1 in cardiovascular disease: Molecular mechanisms and clinical implications. Pharmacol Res. 2024; 208:107369. doi: 10.1016/j.phrs.2023.107369

[44] Escopy S, Chaikof EL. Targeting the P-selectin/PSGL-1 pathway: Discovery of disease-modifying therapeutics for disorders of thromboinflammation. Vessels Thromb Hemost. 2024; 1(3):100015. doi: 10.1016/j.bvth.2024.100015

[45] Di Candia AM, Avila DX, Moreira GR, Villacorta H, Maisel AS. Growth differentiation factor-15, a novel systemic biomarker of oxidative stress, inflammation, and cellular aging: Potential role in cardiovascular diseases. Am Heart J Plus. 2021; 9:100046. doi: 10.1016/j.ahjo.2021.100046