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Will the approval of colchicine lead to a paradigm shift in CVD management?

6th July 2023

Colchicine is a drug traditionally used for an acute attack of gout, but its most recent FDA approval has seen it repurposed for the management of atherosclerotic cardiovascular disease. Clinical writer Rod Tucker considers the evidence and what this means for CVD management.

Most clinicians will be familiar with the use of the anti-inflammatory agent colchicine as a treatment for acute attacks of gout, which is surprising given the lack of good quality evidence for the drug. But, recent events have put the drug on the map for a different purpose.

In late June 2023, the US Food and Drug Administration approved colchicine 0.5 mg for use in patients with cardiovascular disease to reduce adverse cardiac events. But how did a relatively inexpensive and widely used drug suddenly assume an important role in the management of atherosclerotic cardiovascular disease?

The prevailing wisdom is that atherosclerosis is due to the accumulation of cholesterol within the intimal of arteries and necessitates lipid-lowering therapy. An alternative cause, first mooted in 1999, has, until recently, been largely ignored. However, emerging evidence now implies that inflammation, rather than hypercholesterolaemia, is a more important driver of atherosclerosis, hence the rationale for the use of anti-inflammatory agents such as colchicine.

Inflammation and atherosclerosis

The fact that inflammation has a significant role in the development of atherosclerosis arose following the publication of the CANTOS study with canakinumab, which targets the pro-inflammatory agent interleukin-1β. In the trial, the use of canakinumab significantly reduced the primary efficacy endpoint of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death compared to the placebo.

While CANTOS clearly showed how reducing a single inflammatory marker lowered the risk of adverse cardiac events, earlier research had strongly implicated that neutrophils played a part in atherosclerosis.

The possible role of neutrophils in heart disease has been recognised for some time. In 1989, researchers identified an enhanced neutrophil function in patients with ischaemic heart disease although just where neutrophils sat in the pathophysiology of atherosclerosis remained unclear.

It was evident from a study in 1994, that inflammation was present at the immediate site of an atherosclerotic plaque rupture or erosion, leading to speculation that inflammatory changes had a pivotal role in destabilising the fibrous cap of an atherosclerotic plaque, enhancing the risk of coronary thrombosis.

The link between inflammation and neutrophils finally became much more intelligible in 2002, when it was discovered that neutrophil infiltration was actively associated with acute coronary events. Acknowledging the importance of neutrophils in cardiovascular disease, researchers then wondered if a drug that could inhibit the function of neutrophils might be advantageous to patients with cardiovascular disease.

Colchicine works by blocking the assembly and polymerisation of microtubules. These microtubules have numerous roles within cells including maintenance of cell shape, intracellular trafficking, cytokine and chemokine secretion, cell migration and the regulation of ion channels and cell division. But one important consequence of preventing the formation of microtubules is interference with neutrophil adhesion and recruitment to inflamed tissue.

It therefore seemed possible that a drug such as colchicine, might prove invaluable in patients with atherosclerotic cardiovascular disease. Whether this theoretical effect would benefit patients in practice remained to be seen.

Colchicine in cardiovascular disease

The road to the current approval of colchicine in cardiovascular disease was a long one, and the earliest attempts were disappointing.

In a 1992 study, scientists explored the value of the drug at preventing restenosis in patients following angioplasty, although colchicine proved to be no more effective than placebo. Fast forward to 2013, a study among patients who had recently experienced a myocardial infarction found that a daily dose of colchicine 0.5 mg combined with statin therapy appeared to be effective for the secondary prevention of cardiovascular events in patients with stable coronary disease.

Over the next seven years, more positive findings rolled in. For example, the secondary preventative value of colchicine was replicated in a 2019 study. Additionally, colchicine reduced adverse outcomes, in patients with any evidence of coronary disease and in those following either a recent (six to 24 months) or a prior (two to longer than seven years) acute coronary syndrome.

Assimilating the results from available studies, a 2021 meta-analysis of randomised trials with low-dose colchicine (0.5 mg), concluded that the drug lowered the risk of MACE, myocardial infarction, stroke and the need for coronary revascularisation in a broad spectrum of patients with coronary disease.

Given that atherosclerotic cardiovascular disease is largely assumed to be a direct consequence of elevated cholesterol, how important is the presence of inflammation?

A recent analysis, published in The Lancet, directly addressed this question. Researchers turned to three major statins trials in patients with, or at high-risk of, atherosclerotic disease to analyse the relative importance of inflammation and hypercholesterolaemia. The findings were very clear: inflammation rather than elevated levels of LDL cholesterol was the stronger predictor of future risk for both cardiovascular events and death.

While the mainstay of cardiovascular disease management over the past 20 years has been predicated on the notion that hypercholesterolaemia is a major cause, recent data does indeed suggest that inflammation is actually a more relevant prognostic marker.

With cardiovascular diseases still the leading cause of global deaths, the approval of colchicine is recognition of the need for a paradigm shift in the care of patients with the disease, and this will hopefully make a greater impact on overall mortality.

Indian Hedgehog protein release from renal cells linked to development of CKD

2nd June 2023

Elevated levels of the protein Indian Hedgehog, which is released by a subset of aged and injured renal cells, have been identified in patients with chronic kidney disease (CKD) and is therefore a potential therapeutic target for the condition, according to a new study.

Published in the journal Science Translational Medicine, an international research team sought to understand the link between injury and inflammation in patients with CKD. The team hypothesised that signalling from renal epithelial cells activated glioma-associated oncogene 1 expressing cells (Gli1+) to induce fibrosis. But exactly how this process occurred was uncertain.

The ageing process is associated with chronic inflammation and a defective immune response. Conditions such as CKD are accompanied by immunosenescence, with such patients at a higher risk of cardiovascular disease. Previous work revealed a link between increased production of tumour necrosis factor (TNF), CKD and renal failure, but the underlying mechanism remains unclear, which led to the current study.

The researchers identified that leukocyte-derived tumour necrosis factor (TNF) promoted Gli1+ cell proliferation and cardio-renal fibrosis through induction and release of the Indian Hedgehog (IHH) protein from renal epithelial cells. Moreover, inhibition of TNF release led to a reduction in tissue fibrosis and also lowered Gli1+ cell proliferation.

In further work, it also became clear that increased circulating levels of IHH correlated with cardiovascular disease and loss of renal function in patients with CKD. Taken together, the authors suggested their findings indicated that IHH release from TNF-activated renal cells drove the activation and proliferation of Gli1+ expressing cells and was the missing link between inflammation and organ fibrosis.

While these represent preliminary findings, the authors suggested that therapies targeting TNF and/or IHH signalling warrant further investigation to assess their potential in patients with CKD and fibrosis.

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