Page 25 - GTM-4-3

Global Translational Medicine Anti-inflammatory therapy in CVD

Table 1. Comprehensive overview of significant clinical trials exploring the relationship between anti-inflammatory treatments
and cardiovascular disease
Trial name Description Key findings
CIRT Investigated low-dose methotrexate for cardiovascular Methotrexate did not significantly reduce inflammatory markers or
outcomes in patients with prior myocardial infarction or cardiovascular events compared to placebo. The final primary endpoint
coronary artery disease and metabolic conditions. occurrence was similar between the methotrexate and placebo groups.
LODOCO Assessed the efficacy of low-dose colchicine in reducing Significant reduction in MACE with colchicine treatment compared
cardiovascular events post-myocardial infarction. to placebo, highlighting its potential in reducing future cardiovascular
incidents.
COLCOT Evaluated colchicine’s role in post-myocardial infarction Demonstrated a robust reduction in cardiovascular events, advocating
care, focusing on a broad spectrum of cardiovascular for colchicine integration into post-myocardial infarction therapeutic
outcomes. regimens.
CANTOS Explored the effects of canakinumab on patients with Canakinumab significantly reduced the risk of cardiovascular events,
a history of myocardial infarction and a persistent particularly at the 150 mg dose, independent of lipid-lowering effects,
inflammatory response. suggesting benefits in cardiovascular-specific morbidity and mortality.
ZEUS Evaluate ziltivekimab, an IL-6 inhibitor, for reducing The trial is enrolling >6,200 participants to assess whether ziltivekimab
inflammation and MACE in patients with CKD and 15 mg monthly reduces MACE by 20%. Secondary endpoints include
ASCVD with elevated hsCRP levels. kidney function decline and cardiovascular or renal mortality.
Expected completion in 2026.
SOLID-TIMI 52 Investigated darapladib’s role in stabilizing No significant reduction in primary or secondary endpoints, indicating
atherosclerotic plaques post-acute coronary syndrome. that darapladib did not confer significant cardiovascular protection
post-acute coronary syndrome.
Latitude-TIMI 60 Assessed the efficacy and safety of losmapimod in Despite reducing early inflammatory markers, losmapimod did
patients with acute myocardial infarction. not significantly improve long-term clinical outcomes, challenging
the efficacy of p38 MAPK inhibition in post-myocardial infarction
recovery.
Abbreviations: ASCVD: Atherosclerotic cardiovascular disease; CKD: Chronic kidney disease; IL: Interleukin; MACE: Major adverse cardiovascular
events; MAPK: Mitogen-activated protein kinase.

darapladib failed to improve outcomes, with an HR of 1.00 The JAK/STAT pathway is pivotal in converting IL
for major coronary events and 0.99 for cardiovascular signals into gene expression changes that drive immune
death, myocardial infarction, or stroke. Similarly, the processes. Upon receptor binding, ILs activate JAK
26
LATITUDE-TIMI 60 trial investigated losmapimod, a kinases, leading to STAT phosphorylation and nuclear
p38 mitogen-activated protein kinase (MAPK) inhibitor, translocation, where they regulate genes involved
in acute coronary syndrome patients. While losmapimod in inflammation and immune cell differentiation.
29
reduced inflammatory marker levels, it did not translate IL-6 and IL-10, for example, modulate both pro- and
into improved cardiovascular outcomes (HR: 0.99; 95% CI: anti-inflammatory responses through this pathway.
0.91 – 1.08), reinforcing the challenges of targeting single Dysregulation of the JAK/STAT pathway contributes to
inflammatory pathways in atherosclerosis. 27 autoimmune disorders and malignancies, making it a key
target for therapeutic intervention. The MAPK pathway,
8. Newer targets in IL signaling activated by ILs, governs cell proliferation, apoptosis, and
ILs are cytokines produced by leukocytes that regulate cytokine production, influencing immune responses in
30
immune responses by modulating inflammation, cell acute and chronic inflammation. Meanwhile, the NF-κB
proliferation, and differentiation. They bind to specific pathway, critical in immune modulation, is triggered by
receptors, triggering signaling cascades, such as the Janus cytokines such as IL-1 and TNF. Upon activation, NF-κB
kinase signal transducer and activator of transcription translocates to the nucleus, promoting the transcription of
(JAK/STAT), MAPK, and NF-κB, influencing immune pro-inflammatory genes essential for immune defense but
cell function and inflammatory gene expression. Their also implicated in chronic inflammatory diseases, such as
28
dual ability to activate or suppress immune responses atherosclerosis. 31
makes them central to autoimmune diseases, cancers, and Several ILs play crucial roles in cardiovascular
cardiovascular pathologies. Dysregulation of IL signaling inflammation. IL-1, IL-6, and IL-18 contribute to vascular
can lead to chronic inflammation and contribute to disease damage and plaque instability, accelerating atherosclerosis.
progression, making them attractive therapeutic targets. Emerging cytokines, such as IL-17F, IL-33, IL-34, and

Volume 4 Issue 3 (2025) 17 doi: 10.36922/GTM025100024