Role of anti-inflammatory agent colchicine in atherosclerotic cardiovascular disease

Abstract

Colchicine is an anti-inflammatory alkaloid that reduces cardiovascular events through its actions on the interleukin(IL)-1β/IL-6/C-reactive protein pathway, which promotes the degradation and rupture of atherosclerotic plaques. Low-dose colchicine (0.5 mg/day) has been shown to decrease major adverse cardiovascular events (MACE) by 31% among patients with stable atherosclerosis and 23% among those after a recent myocardial infarction. In patients with coronary artery disease (CAD) already taking a statin, colchicine in conjunction with lipid-lowering therapy has additionally been shown to provide a larger benefit with respect to secondary prevention of MACE. The drug is contraindicated in patients with renal or hepatic impairment and should be avoided in patients taking strong cytochrome P450 3A4 or P-glycoprotein inhibitors. Low-dose colchicine was recently approved by the United States Food and Drug Administration in 2023 to reduce the risk of stroke, coronary revascularization, myocardial infarction, and cardiovascular death among patients with atherosclerotic disease or multiple risk factors. This article focuses on the use of colchicine and its anti-inflammatory effects in preventing MACE among patients with CAD and patients without CAD with multiple risk factors.

Core Tip: Inflammation is now recognized as an essential component of atherosclerosis, and the anti-inflammatory agent colchicine, through a variety of actions, suppresses this response. Results from a meta-analysis of several randomized controlled trials that evaluated colchicine’s efficacy on cardiovascular outcomes led to its recent approval by the United States Food and Drug Administration for the management and prevention of atherosclerotic cardiovascular disease. It has been shown to reduce the risk of recurrent major adverse cardiovascular events, and clinical data now supports its use for secondary prevention in patients with established coronary artery disease, presumably due to its anti-inflammatory properties.

INTRODUCTION

Within the past several decades, morbidity and mortality from coronary artery disease (CAD) have decreased through the advent of medications and lifestyle interventions[1-3]. Despite the management of known risk factors such as hyperlipidemia, hypertension, tobacco use, diabetes mellitus, and obesity, CAD remains the primary cause of mortality and disability-adjusted life years lost worldwide[4,5]. This burden of disease has a disproportionate impact on middle and low-income nations, resulting in over 7 million fatalities and 129 million disability-adjusted life years each year[4-7]. A significant proportion of residual risk leading to atherosclerosis is related to uncontrolled inflammation[8-10].

Inflammation plays a vital role in the development of CAD[11]. The progression of vulnerable plaques is associated with neutrophil-driven endothelial dysfunction, leading to heightened permeability to lipoproteins and their accumulation beneath the endothelium, along with the recruitment of leukocytes and activation of platelets, which increases the risk of plaque rupture[12-16]. Several studies have shown that elevated C-reactive protein (CRP), a marker of inflammation, is associated with the development of atherosclerosis even in patients on statin therapy with low-density lipoprotein (LDL)-cholesterol < 70 mg/dL[17-19]. Several clinical trials have demonstrated that colchicine, an anti-inflammatory agent frequently used to treat gout and pericarditis, among other inflammatory conditions, reduces major adverse cardiovascular events (MACE) even in patients with stable CAD and a recent acute myocardial infarction (MI)[20-22]. In this article, we provide a scoping review of colchicine and its mechanism of action, biochemical and molecular targets in various cardiovascular conditions, and safety and efficacy in the treatment of CAD.

MECHANISM OF ACTION OF COLCHICINE

Colchicine facilitates the prevention and treatment of CAD through various biochemical avenues[23]. Dysfunction of the endothelium plays a crucial role in the development and progression of atherosclerosis[23,24]. The drug prevents endothelial dysfunction through various mechanisms of action contingent on the dosage[25,26]. At reduced doses, it interferes with microtubule function and hinders cell migration, whereas at elevated doses, it obstructs mitosis[27,28]. Colchicine has also been shown to decrease the levels and expression of the tissue factor protein and gene, respectively, which play a vital role in the pathogenesis of coronary thrombosis induced by oxidized LDL[29,30]. By suppressing the upregulation of tissue factor, colchicine demonstrates protective benefits in atherosclerosis, providing an additional therapeutic option[29-31].

Colchicine also plays a role in atherosclerosis by inhibiting the chemotaxis of macrophages and neutrophils through the suppression of interleukin (IL)-18 and C-type lectin-like receptor production[32,33]. Macrophages accumulate in damaged vessel walls and produce foam cells through the uptake of modified lipids[34]. The drug hinders the expression of adhesion molecules L and E-selectin by promoting microtubule dysfunction and obstructing the advancement of plaque development (Figure 1)[35,36]. Research has shown that colchicine administered through nanoparticles coated with macrophage membranes can prevent the formation of foam cells[37]. Colchicine elevates cyclic adenosine monophosphate levels in leukocytes, which in turn reduces IL-1 production[38,39]. Furthermore, it reduces the generation of neutrophil extracellular traps, thereby inhibiting the release of inflammatory cytokines from injured macrophages and endothelial cells[38-40]. This mechanism is especially advantageous for patients experiencing acute coronary syndrome who have received percutaneous coronary intervention[36-38,40,41].

Figure 1.

Schematic diagram showing the regulatory mechanisms of colchicine in response to inflammation. COL: Colchicine; IL: Interleukin.

Lastly, colchicine suppresses plaque formation through the inhibition of smooth muscle cells (SMCs) and platelet activation[38-42]. SMCs play a crucial role in vascular contraction and the synthesis of extracellular matrix proteins such as proteoglycans and collagen (COLL)[43,44]. Dysregulation of vascular SMCs is a hallmark feature of atherosclerosis[45]. Lipid molecules accumulate in the sub-endothelium, which triggers the proliferation and migration of SMCs, initiating plaque formation[43-46]. Extracellular matrix proteins are then secreted, leading to the formation of fibrous caps within the atheroma[44-47]. SMCs also interact with oxidized LDL to form foam cells within plaques that then undergo apoptosis, releasing proinflammatory cytokines and further facilitating atherosclerotic plaque formation[43-48]. Colchicine disrupts this process by inhibiting microtubule polymerization[49]. Platelet activation is known to promote the pathogenesis of atherosclerosis, as seen in unstable angina and MI[45-50]. Upon activation, platelets cluster together and release proinflammatory cytokines, resulting in thrombus formation[46-51]. The processes of microtubule depolymerization and polymerization are essential to platelet activation[45-52]. Colchicine disrupts this mechanism, consequently inhibiting the release of inflammatory cytokines and the aggregation of platelets[53]. A study conducted by Cimmino et al[54] investigated whether colchicine interfered with platelet aggregation by action on cytoskeleton rearrangement. In the experiment, platelets obtained from healthy volunteers were activated using adenosine diphosphate (ADP), COLL, and thrombin-activating receptor peptide (TRAP), both with and without a 10 μM colchicine pretreatment. Following the stimulation, aggregation was assessed through light aggregometry over time. Results revealed that colchicine pretreatment significantly reduced ADP/COLL/TRAP-induced platelet aggregation. The effects appeared to be mediated by microtubule depolymerization, and cytoskeleton disarrangement associated with the inactivation of myosin phosphatase targeting subunit and LIM domain kinase 1 that interfered with coilin activity. A notable limitation of the experiment was that it was a mechanistic study conducted in vitro. As such, more targeted clinical trials are needed to accurately determine the in vivo colchicine dosage and duration of treatment required to achieve cardiac benefit in both the short and long term.

BIOCHEMICAL AND MOLECULAR TARGETS OF COLCHICINE

There are several molecular mechanisms through which colchicine exerts its anti-inflammatory effects. The primary mechanism of action that has been extensively researched regarding colchicine is its capacity to bind to tubulins, which consequently inhibits the formation and polymerization of microtubules[55,56]. Colchicine particularly blocks mitotic cells in metaphase[55-57]. It attaches to soluble tubulin, creating tubulin-colchicine complexes that adhere to the ends of microtubules, thereby inhibiting polymerization[55,57]. At low concentrations, the drug limits microtubule growth, while at higher concentrations, it promotes microtubule depolymerization[55-58]. It selectively accumulates within neutrophils and erythrocytes, which lack P-glycoproteins that typically facilitate clearance[53-59]. The buildup within neutrophils hinders chemotaxis and triggers the release of adhesion molecules, including L-selectin, consequently obstructing additional recruitment of neutrophils[35,36,56,58,59]. Colchicine has also been demonstrated to inhibit neutrophil adhesion and mobility during crystal-induced neutrophil activation through the selective inhibition of tyrosine phosphorylation[35,36,60]. A study conducted by Popa-Nita et al[61] demonstrated that colchicine diminishes the crystal-induced tyrosine phosphorylation of Tec, which is likely the primary kinase involved in the activation of neutrophils by crystals. Lastly, colchicine suppresses monosodium urate crystal-induced NACHT-LRRPYD-containing protein 3 inflammasomes, responsible for caspase-1 activation and subsequent IL-1β and IL-18 processing and release[62,63]. The mechanism through which colchicine achieves this inhibition still remains unknown. These variations in the mechanism of action of the drug are thought to play a role in its beneficial effects on atherosclerosis[59-64]. The long-term use of low-dose colchicine (0.5 mg daily) is safe and well tolerated[57-59]. More serious adverse effects, such as bone marrow suppression and myotoxicity, are likely to occur at higher doses in patients with liver or renal impairment[57-59,61,63,64].

ATHEROSCLEROSIS, INFLAMMATION, AND COLCHICINE

Atherosclerosis progresses through the accumulation of inflammatory cells and cholesterol within the arterial wall, leading to the formation of vessel-occluding plaques that can result in chronic ischemia and risk of severe cardiovascular complications, including MI and stroke, as a consequence of acute plaque rupture[65,66]. This process also involves an inflammatory response to cholesterol, which leads to the formation of crystals within arterial walls[65-67]. Thus, despite the use of potent cholesterol-reducing agents, patients face an elevated lifetime risk of recurring MACE due to inadequate control of the inflammatory process[68-70].

Recent clinical trials such as COLCOT and CANTOS have provided substantial evidence that reducing the inflammatory response in patients with atherosclerotic cardiovascular disease leads to better clinical outcomes (Table 1)[21,71-75]. Despite the efficacy of IL-1β inhibitor canakinumab in reducing the rate of recurrent cardiovascular events compared to placebo in the CANTOS trial, low-dose colchicine is the sole anti-inflammatory agent approved by the FDA for clinical application in patients diagnosed with established CAD[71,72,76]. A meta-analysis conducted by Zhou et al[77] of five large randomized controlled trials that included more than 14000 patients found that early long-term use of low-dose colchicine in patients who suffer an acute MI decreases the risk of MACE through its anti-inflammatory effects. Although it is now known that colchicine offers protective cardiovascular effects, the exact mechanism through which this occurs is still not well understood.

Table 1.

Summary of Colchicine trial outcomes in atherosclerotic cardiovascular disease

Trial number	Trial name/year	Official title	Details	Outcome	Notes
ACTRN 12610000293066	LoDoCo/2013	Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease	n = 532; Patients diagnosed with stable, angiographically confirmed CAD who have maintained clinical stability for a minimum of six months were randomly assigned to receive either standard treatment in conjunction with 0.5 mg of daily colchicine or standard treatment alone	Colchicine had a lower composite outcome of OHCA, ACS, or non-cardioembolic ischemic stroke vs control (5.3% vs 16%; HR, 0.33; 95%CI: 0.18-0.59; P < 0.001)	The most common side effect was GI disturbance
NCT02551094	COLCOT/2019	Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction	n = 4745; Patients within 30 days post MI were randomized to either standard therapy plus placebo or standard therapy plus 0.5 mg daily colchicine	Lower incidence of MACE in the colchicine group (5.5% vs 7.1%; HR, 0.77; 95%CI: 0.61-0.96; P = 0.02)	The most common side effect was GI disturbance
ACTRN12615000861550	COPS/2020	Colchicine in Patients with Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial	n = 795; Patients presenting with ACS with evidence of CAD (angiographically managed with PCI or medical therapy) were randomized to receive either standard therapy plus colchicine (0.5 mg BID for the first month post ACS, then 0.5 mg daily for 11 months) or placebo plus standard therapy	There was no statistically significant difference between the two groups (HR, 0.65; 95%CI: 0.38-1.09; P = 0.1) in the primary outcome (i.e., a composite of all-cause mortality, ACS [STEMI/NSTEMI/UA], ischemia-driven urgent revascularization, and noncardioembolic ischemic stroke). However, the colchicine arm showed lower incidence of the primary outcome when all-cause mortality was replaced with CV mortality (5% vs 9.5%; HR, 0.51; 95%CI: 0.29-0.89; P = 0.019)	The most common side effect was GI disturbance
ACTRN12614000093684	LoDoCo2/2020	Colchicine in Patients with Chronic Coronary Disease	n = 5552; Patients with stable CAD (angiographically or CAC score ≥ 400 AU) who were clinically stable for ≥ 6 months were randomized to either standard therapy plus 0.5 mg daily colchicine or to standard therapy plus placebo. A total of 3,179 patients had ACS for a duration of 24 months or more prior to randomization	Colchicine demonstrated a reduced occurrence of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization compared to placebo (6.8% vs 9.6%; HR, 0.69; 95%CI: 0.57-0.83; P < 0.001)	The colchicine group experienced a higher occurrence of non-cardiovascular deaths, although this was not statistically significant (incidence, 0.7 compared to 0.5 events per 100 person-years; HR, 1.51; 95%CI: 0.99-2.31)
NCT03048825	CLEAR SYNERGY/2024	Colchicine in Acute Myocardial Infarction	n = 7062; Patients within 72 hours post MI were randomized to either standard therapy plus 0.5 mg daily colchicine or to standard therapy plus placebo	There was no significant difference in MACE outcomes observed between the two groups (9.1% compared to 9.3%; HR, 0.99; 95%CI: 0.85-1.16; P = 0.93). Additionally, there was no notable difference in all-cause mortality (4.6% compared to 5.1%; HR, 0.90; 95%CI: 0.73-1.12)	A higher incidence of diarrhea was reported in the colchicine group (6.6% vs 10.2%; P < 0.001)

LoDoCo: Low-Dose Colchicine; CAD: Coronary artery disease; OHCA: Out-of-hospital cardiac arrest; ACS: Acute coronary syndrome; HR: Hazard ratio; CI: Confidence interval; GI: Gastrointestinal tract; COLCOT: Colchicine Cardiovascular Outcomes Trial; MI: Myocardial infarction; MACE: Major adverse cardiac event; COPS: Colchicine to Improve Cardiovascular Outcomes in ACS Patients; PCI: Percutaneous coronary intervention; BID: Twice daily; STEMI: ST-segment elevation myocardial infarction; NSTEMI: Non-ST-segment elevation myocardial infarction; UA: Unstable angina; CV: Cardiovascular; LoDoCo2: Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease 2; CAC: Coronary artery calcium; AU: Agatston unit; CLEAR SYNERGY: Colchicine in Acute Myocardial Infarction.

Perhaps the most recognized action of colchicine on inflammation includes its inhibitory effects on the function of neutrophils[78]. It is also known to affect the innate properties of the endothelium, SMCs, and macrophages, which reduce the interaction between platelets and neutrophils, mitigate plaque growth, improve stability, and lower the risk of thrombotic occlusion[59-64,68-70,79]. Bulnes et al[80] expanded on accumulating evidence from clinical and animal research that demonstrates the inhibitory effect of colchicine on the NLRP3 inflammasome. This protein complex, when activated in inflammatory cells, enhances the production of pro-atherosclerotic and highly inflammatory cytokines, specifically IL-18 and IL-1β. Crystals that develop due to the accumulation of cholesterol in plaque serve as a triggering factor for the activation of NLRP3. Another research article by Abideen et al[81] detailed an inverse relationship between the formation and expansion of cholesterol crystals in vitro and the dose of colchicine used, potentially elucidating the compound’s indirect effects on inhibiting NLRP3 activation, which ultimately may limit the risk of acute plaque rupture. In the study, in vitro tests conducted on rat and rabbit biological membranes, observed through scanning electron microscopy, demonstrated that cholesterol crystals could distort and protrude through the tissue due to their sharp geometric edges. This observation was found to be analogous to ex vivo results from human plaques and arterial tissues, which were prepared using vacuum dehydration for scanning electron microscopy, revealing cholesterol crystals that disrupt the plaque and penetrate the intimal surface. Abideen et al[81] and colleagues provided a novel mechanism suggesting that colchicine may reduce the risk of acute plaque rupture by altering cholesterol crystal production and slowing the rate of crystal formation.

FUTURE PERSPECTIVES ON COLCHICINE AS THERAPY FOR CAD

Despite the considerable advancements made in comprehending inflammation and its contribution to the pathogenesis of atherosclerosis, there remain knowledge gaps, especially concerning the precise mechanism through which certain agents, like colchicine, mitigate MACE following an acute MI[82-86]. In clinical practice, the harmful impact of inflammation in CAD can be confirmed by randomizing patients to receive either anti-inflammatory agents or a placebo and monitoring the occurrence of cardiovascular events over time. The CANTOS trial was the first to validate the inflammatory hypothesis in relation to CAD, evaluating patients who had experienced a previous MI and exhibited a high-sensitivity CRP level of 2 mg or greater per liter. It is not surprising that the experimental group experienced advantages from the anti-inflammatory treatment. Conversely, the event rates in the placebo groups of both the CANTOS and CIRT trials were comparable, even though the CIRT trial did not include high-sensitivity CRP as a criterion for inclusion[72,87].

The key point to emphasize in the broader context is that there is no validated indicator of inflammation, including high-sensitivity CRP, deemed effective as a resource for clinical decision-making. This may be linked to chronic subclinical inflammation in individuals with previous cardiovascular incidents or other unidentified inflammatory disorders, and potentially colchicine due to its various effects, particularly its direct impact on blood vessels and platelets. More research is needed to ascertain if the advantages of colchicine are associated with the circulating levels of inflammatory biomarkers and baseline cardiovascular risk. Additional research is also needed to elucidate the exact mechanism by which colchicine exerts its anti-inflammatory effects in CAD. Furthermore, studies are required to determine the optimal timing of colchicine in the short term following a MI. It would also be intriguing to evaluate whether colchicine is advantageous in primary prevention (i.e., in patients without symptomatic CAD or previous cardiovascular events).

CONCLUSION

In summary, most patients with atherosclerotic cardiovascular disease possess residual inflammatory risk, which predisposes MACE, especially after an acute MI. These patients remain at significant risk despite effective cholesterol-lowering therapies. Colchicine, particularly through its suppressive action on the NLRP3 inflammasome, reduces inflammatory cytokine response in atherosclerosis, which ultimately decreases the risk of plaque progression and subsequent thrombosis. As such, anti-inflammatory therapy in the form of colchicine, particularly in patients with CAD, should be seriously considered by preventative cardiologists if there are no contraindications to treatment, such as severe renal or liver dysfunction.