https://orcid.org/0000-0001-9191-6695
Abstract
In type 1 diabetes, average life expectancy is reduced by ˃10 years as compared with outside of diabetes. Residual cardiovascular risk defines high cardiovascular event rate despite modern, guideline-recommended standard of care of established risk factors like hypertension, dyslipidaemia, and glycaemic control, and it adds importantly to these lost years of life in type 1 diabetes due to atherosclerotic cardiovascular diseases like myocardial infarction and ischaemic stroke. With a growing understanding of inflammation as an important driver of atherosclerotic cardiovascular disease, residual inflammatory risk is a novel and common risk factor and a promising target for lowering residual cardiovascular risk in type 1 diabetes. Interestingly, the inexpensive anti-inflammatory agent colchicine reduced the risk of major adverse cardiovascular events by 25% in cardiovascular outcome trials in the secondary prevention of atherosclerotic cardiovascular disease. Here, we summarize the role of inflammation as a driver of atherosclerosis and review current evidence linking inflammation and atherosclerotic cardiovascular disease in type 1 diabetes. Also, we provide an overview of the evidence base for targeting residual inflammatory risk with colchicine for lowering residual cardiovascular risk in type 1 diabetes.
ASCVD, atherosclerotic cardiovascular disease; CRP, C-reactive protein; CV, cardiovascular; MACE, major adverse cardiovascular event; T1D, type 1 diabetes.
Introduction
A total of 50 million people worldwide living with type 1 diabetes are at very high risk of cardiovascular (CV) disease (CVD), and they have a reduced average life expectancy of ˃10 years as compared with people without diabetes.1–3 Major adverse CV events (MACE) such as CV death, myocardial infarction (MI), and stroke as a result of atherosclerotic CVD (ASCVD) contribute importantly to these lost years of life.3 Insulin therapy is the bedrock of the pharmaceutical management of type 1 diabetes, and glycaemic control reduces the risk of microvascular and macrovascular complications.4,5 However, the guideline-recommended standard of care (SoC) of CV risk, including control of hypertension and dyslipidaemia next to glycaemic control, is still insufficient to address the high risk of ASCVD in type 1 diabetes.6,7 Relevant to type 1 diabetes, the concept of residual CV risk defines high CV event rates despite the guideline-recommended SoC of established CV risk factors like hypercholesterolaemia, hypertension, and diabetes.8 Individuals with type 1 diabetes who are treated according to SoC ought to be considered at residual CV risk as they are classified as at particularly high CV risk in international guidelines.9,10 With a growing understanding of inflammation as an important driver of ASCVD,11residual inflammatory risk constitutes a novel CV risk factor with an estimated prevalence of 40% both in type 1 diabetes and outside this disease.12,13 Residual inflammatory risk is a promising target for lowering residual CV risk and risk of MACE,8 and it is defined by elevated circulating levels of C-reactive protein (CRP), i.e. ≥2 mg/L as assessed by a high-sensitivity CRP assay.8 Recently, we reported that residual inflammatory risk was associated with obesity and dyslipidaemia but not with glycaemic control and hypertension in a study population with high CV risk and type 1 diabetes.12 The concept of residual inflammatory risk offers a new way of addressing the residual CV risk observed in type 1 diabetes, and the inexpensive anti-inflammatory agent colchicine has been observed to reduce the risk of MACE by 25% in CV outcome trials in the secondary prevention of ASCVD.14 No dedicated CV outcome trial has investigated colchicine in diabetes, but around 20% of participants had type 2 diabetes at baseline in reported trials,14 alluding to colchicine's potential efficacy in type 1 diabetes. Thus, cardiovascular benefits with colchicine would be expected in type 1 diabetes, but usage of colchicine in this disease requires specific evaluation before implementation for several reasons. Firstly, the anti-inflammatory effect of colchicine and its beneficial effect on low-grade inflammation may differ in type 1 diabetes. Secondly, colchicine's potential modulating effect on insulin sensitivity and, thus, interaction with insulin therapy needs to be established. Thirdly, the safety of colchicine in type 1 diabetes with a specific focus on the risk of acute complications, like hypoglycaemia and ketoacidosis needs to be established. That is, any influence of anti-inflammatory therapy with colchicine on insulin sensitivity and consequently, insulin dosage, plasma glucose levels, and risk of hypoglycaemia may only be evaluated in a dedicated trial in this disease. Below, we summarize the role of inflammation as a driver of ASCVD and review current evidence linking inflammation and ASCVD in type 1 diabetes. Also, we provide an overview of the evidence base for targeting residual inflammatory risk with colchicine for lowering the risk of ASCVD in type 1 diabetes.
Inflammation drives atherosclerosis and atherosclerotic cardiovascular disease
Inflammation is an important driver of atherosclerosis. From the very first formation of a fatty streak in the vessel wall, activation of the endothelial cells leads to an expression of leucocyte adhesion molecules and ensuing recruitment of leucocytes and a localized inflammatory response.11,15,16 Accumulation of low density lipoprotein (LDL) cholesterol seems causal in triggering this cascade of events, yet the emphasis is put on our incomplete understanding of the triggering factors for atheroma formation.11,15,16 During the progression from fatty streak to advanced atheroma, a balance between pro- and anti-inflammatory stimuli influences the course of atherosclerosis. Acute inflammatory reactions may seemingly incite progression in the atheroma. Distant inflammatory reactions to e.g. infections or inflammatory diseases, like rheumatoid arthritis, release pro-inflammatory cytokines that circulate in the bloodstream to the site of the atheroma with local amplification of the inflammatory process here.11,15,16 Ultimately, inflammation may destabilize the atheroma and precipitate acute coronary syndrome, and it responds to cardiomyocyte necrosis with a potential increased risk of recurrent events following MI.8,11,17 Indeed, the inflammatory hypothesis of atherosclerosis was corroborated by several key CV outcome trials with anti-inflammatory agents targeting the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP-3) inflammasome, interleukin (IL) 1β, IL-6, and CRP pathway.18–20 The NLRP-3 inflammasome is an integral part of the innate immune system responding to extracellular stimuli from both pathogens and danger-associated molecular patterns such as cholesterol crystals. The NLRP-3 inflammasome activates caspase-1 enzymatic activity with subsequent cleavage of pro-IL-1β and pro-IL-18 to active IL-1β and IL-18. IL-1β is an important stimulus of IL-6 secretion that itself stimulates the production and secretion of CRP.16 Of the components of this pivotal inflammatory pathway of the innate immune system, IL-6 seems causal in atherosclerosis and CRP seems a biomarker of CV risk without a causal connection to the process of atherosclerosis.8,21–23 Beyond this pathway, tumour necrosis factor α is a central proinflammatory cytokine that modulates plaque formation and growth.15,16 It is secreted from various cell types in the plaque, including resident macrophages, neutrophils, and B and T cells.15,16
Inflammation seems to drive atherosclerosis to a greater degree in diabetes than outside diabetes. Substantiated by the scarce autopsy data available, atheromas from corpses of persons with diabetes appeared more laden with lipids, macrophages, and thrombi.24 Also, necrotic cores were larger and more heavily laden with inflammatory infiltrates of macrophages and T lymphocytes as compared with atheromas from corpses of non-diabetic individuals.25 Worryingly, systemic inflammation seems present even in young individuals with type 1 diabetes and appears within the first years of diagnosis of type 1 diabetes. Here, elevated levels of IL-6, CRP, and fibrinogen have been observed. They were either independent of glycaemic control and obesity and correlated with an atherogenic lipid profile,26 or they positively associated with glycated haemoglobin, body mass index, and C-peptide levels.27,28 Also, levels of the soluble IL-2 receptor, cluster of differentiation 40 ligands, and serum amyloid A appear elevated in type 1 diabetes as compared with non-diabetic individuals.29–32 The link between inflammation and the risk of ASCVD in type 1 diabetes is suggested by both experimental studies and prospective cohorts. Subclinical atherosclerosis, i.e. increased levels of mean and maximum intima-media thickness, correlated with increased CRP levels in 55 individuals with type 1 diabetes (mean age 22 years and diabetes duration 14 years) as compared with 75 age-matched healthy controls.33 In a post hoc analysis of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) trial, an increased compound score of CRP and fibrinogen and adipokines/cytokines, including IL-6, associated with subclinical atherosclerosis measured by carotid intima-media thickness after 12 years of follow-up.34 In other studies, elevated levels of lipoprotein-associated phospholipase A2 and CRP correlated with risk of coronary artery disease,35 and increased soluble IL-2 receptor levels correlated with atherosclerosis assessed by coronary artery calcification.29 Also, reduced levels of adiponectin, a hormone secreted from primarily adipocytes with insulin-sensitizing, anti-inflammatory, and cardioprotective effects,36 are inversely associated with increased CV risk in type 1 diabetes.37,38 Additionally, in type 1 diabetes, systemic inflammation is linked with risk of ASCVD levels by serum endogenous secretory receptor for advanced glycation end-products,39 plasma fibrinogen,40 modified apolipoprotein B-rich immune complexes,41 connective tissue growth factor,42 resistin,43 and serum and urinary orosomucoid.44 Finally, type 1 diabetes is an autoimmune disease with abnormal immune function as part of its aetiology.45,46 Interestingly, a 26-year follow-up of the DCCT/EDIC study suggested potential roles for autoimmune mechanisms in the development of atherosclerosis (coronary artery calcification) and ASCVD events.47
Anti-inflammatory therapy reduces cardiovascular risk
Anti-inflammatory agents were first proven to independently reduce risk of CV events in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial reported in 2017. Here, the monoclonal IL-1β antibody canakinumab at a 150 mg dosage reduced risk of MACE (a composite endpoint of non-fatal stroke, non-fatal MI, and CV death) by 15% [95% confidence interval (CI) 0.74–0.98] as compared with placebo following median 3.7 years of treatment in persons with previous MI and CRP ≥2 mg/L (Table 1).18 Canakinumab, similarly to colchicine, targets the NLRP-3 inflammasome, IL-1β, IL-6, and CRP pathway. On the contrary, in the Cardiovascular Inflammation Reduction Trial (CIRT) trial, low-dose methotrexate at 15–20 mg once weekly did not lower risk of MACE (non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or CV death) as compared with placebo after median 2.3 years of treatment in individuals with stable coronary disease and concomitant type 2 diabetes or metabolic syndrome (Table 1).48 Speculations into why methotrexate did not influence CV risk included: (i) residual inflammatory risk (CRP ≥2 mg/L) was not an inclusion criterion in CIRT (median baseline CRP 1.5 mg/L in CIRT vs. 4.2 mg/L in CANTOS), and (ii) methotrexate does not target the NLRP-3 inflammasome, IL-1β, IL-6, and CRP pathway as evidenced by lack of reduction of these biomarkers in CIRT as opposed to 35%–40% reductions from baseline in CANTOS and as compared with placebo, respectively.48 Conclusively, only drugs like canakinumab and colchicine targeting the NLRP-3 inflammasome, IL-1β, IL-6, and CRP pathway have been shown to reduce risk of ASCVD.
Overview of cardiovascular outcome trials evaluating anti-inflammatory therapy
| LoDoCo2 | COLCOT | CANTOS | CIRT | |
|---|---|---|---|---|
| Trial design | Randomized, double-blind trial | Randomized, double-blind trial | Randomized, double-blind trial | Randomized, double-blind trial |
| Trial size | 5522 | 4745 | 10 061 | 4786 |
| Study population | Chronic coronary disease, clinically stable >6 months | MI within 30 days of enrolment | Previous MI and CRP ≥2 mg/L | Previous MI or multivessel coronary disease and type 2 diabetes or the metabolic syndrome |
| Active treatment | Colchicine 0.5 mg QD | Colchicine 0.5 mg QD | Canakinumab 50 mg, 150 mg, or 300 mg every third month | Methotrexate 15 or 20 mg OW and 1 mg of folate QD |
| Comparator | Placebo | Placebo | Placebo | Placebo and 1 mg folate QD |
| Primary endpoint definition | Composite of CV death, MI, ischaemic stroke, or ischaemia-driven coronary revascularization | Composite of CV death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization | Composite of CV death, non-fatal MI, non-fatal stroke | Composite of CV death, non-fatal MI, non-fatal stroke |
| Follow-up (median) | 29 months | 23 months | 3.7 years | 2.3 years |
| Age (years) | 66 | 61 | 61 | 66 |
| Female sex (%) | 15 | 19 | 25 | 19 |
| Diabetes (unspecified) (%) | 18 | 20 | 40 | 33 |
| Primary endpoint result | 0.69 (0.57–0.83) | 0.77 (0.61–0.96) | 0.88 (0.79–0.97) | 1.01 (0.82–1.25) |
| 3P-MACE* | 0.72 (0.57–0.92) | 0.85 (0.66–1.10)‡ | 0.88 (0.79–0.97) | 1.01 (0.82–1.25) |
| MI | 0.70 (0.53–0.93) | 0.91 (0.68–1.21) | 0.84 (0.73–0.97) | 0.99 (0.76–1.29) |
| Stroke | 0.66 (0.35–1.25) | 0.26 (0.10–0.70) | 0.93 (0.72–1.20) | 0.91 (0.54–1.52) |
| CV death | 0.80 (0.44–1.44) | 0.84 (0.46–1.52) | 0.87 (0.73–1.05) | 1.14 (0.76–1.72) |
| Non-CV death | 1.51 (0.99–2.31) | 1.16 (0.64–2.10) | 0.97 (0.79–1.19) | – |
| All-cause death | 1.21 (0.86–1.71) | 0.98 (0.64–1.49) | 0.94 (0.83–1.06) | 1.16 (0.87–1.56) |
| LoDoCo2 | COLCOT | CANTOS | CIRT | |
|---|---|---|---|---|
| Trial design | Randomized, double-blind trial | Randomized, double-blind trial | Randomized, double-blind trial | Randomized, double-blind trial |
| Trial size | 5522 | 4745 | 10 061 | 4786 |
| Study population | Chronic coronary disease, clinically stable >6 months | MI within 30 days of enrolment | Previous MI and CRP ≥2 mg/L | Previous MI or multivessel coronary disease and type 2 diabetes or the metabolic syndrome |
| Active treatment | Colchicine 0.5 mg QD | Colchicine 0.5 mg QD | Canakinumab 50 mg, 150 mg, or 300 mg every third month | Methotrexate 15 or 20 mg OW and 1 mg of folate QD |
| Comparator | Placebo | Placebo | Placebo | Placebo and 1 mg folate QD |
| Primary endpoint definition | Composite of CV death, MI, ischaemic stroke, or ischaemia-driven coronary revascularization | Composite of CV death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization | Composite of CV death, non-fatal MI, non-fatal stroke | Composite of CV death, non-fatal MI, non-fatal stroke |
| Follow-up (median) | 29 months | 23 months | 3.7 years | 2.3 years |
| Age (years) | 66 | 61 | 61 | 66 |
| Female sex (%) | 15 | 19 | 25 | 19 |
| Diabetes (unspecified) (%) | 18 | 20 | 40 | 33 |
| Primary endpoint result | 0.69 (0.57–0.83) | 0.77 (0.61–0.96) | 0.88 (0.79–0.97) | 1.01 (0.82–1.25) |
| 3P-MACE* | 0.72 (0.57–0.92) | 0.85 (0.66–1.10)‡ | 0.88 (0.79–0.97) | 1.01 (0.82–1.25) |
| MI | 0.70 (0.53–0.93) | 0.91 (0.68–1.21) | 0.84 (0.73–0.97) | 0.99 (0.76–1.29) |
| Stroke | 0.66 (0.35–1.25) | 0.26 (0.10–0.70) | 0.93 (0.72–1.20) | 0.91 (0.54–1.52) |
| CV death | 0.80 (0.44–1.44) | 0.84 (0.46–1.52) | 0.87 (0.73–1.05) | 1.14 (0.76–1.72) |
| Non-CV death | 1.51 (0.99–2.31) | 1.16 (0.64–2.10) | 0.97 (0.79–1.19) | – |
| All-cause death | 1.21 (0.86–1.71) | 0.98 (0.64–1.49) | 0.94 (0.83–1.06) | 1.16 (0.87–1.56) |
Overview of CV outcome trials evaluating anti-inflammatory therapy. *3P-MACE defined as CV death, non-fatal MI, or non-fatal stroke. ‡Including resuscitated cardiac arrest. 3P, 3-point; CRP, C-reactive protein; CV, cardiovascular; MACE, major adverse CV event; MI, myocardial infarction; QD, once daily; OW, once weekly.
Overview of cardiovascular outcome trials evaluating anti-inflammatory therapy
| LoDoCo2 | COLCOT | CANTOS | CIRT | |
|---|---|---|---|---|
| Trial design | Randomized, double-blind trial | Randomized, double-blind trial | Randomized, double-blind trial | Randomized, double-blind trial |
| Trial size | 5522 | 4745 | 10 061 | 4786 |
| Study population | Chronic coronary disease, clinically stable >6 months | MI within 30 days of enrolment | Previous MI and CRP ≥2 mg/L | Previous MI or multivessel coronary disease and type 2 diabetes or the metabolic syndrome |
| Active treatment | Colchicine 0.5 mg QD | Colchicine 0.5 mg QD | Canakinumab 50 mg, 150 mg, or 300 mg every third month | Methotrexate 15 or 20 mg OW and 1 mg of folate QD |
| Comparator | Placebo | Placebo | Placebo | Placebo and 1 mg folate QD |
| Primary endpoint definition | Composite of CV death, MI, ischaemic stroke, or ischaemia-driven coronary revascularization | Composite of CV death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization | Composite of CV death, non-fatal MI, non-fatal stroke | Composite of CV death, non-fatal MI, non-fatal stroke |
| Follow-up (median) | 29 months | 23 months | 3.7 years | 2.3 years |
| Age (years) | 66 | 61 | 61 | 66 |
| Female sex (%) | 15 | 19 | 25 | 19 |
| Diabetes (unspecified) (%) | 18 | 20 | 40 | 33 |
| Primary endpoint result | 0.69 (0.57–0.83) | 0.77 (0.61–0.96) | 0.88 (0.79–0.97) | 1.01 (0.82–1.25) |
| 3P-MACE* | 0.72 (0.57–0.92) | 0.85 (0.66–1.10)‡ | 0.88 (0.79–0.97) | 1.01 (0.82–1.25) |
| MI | 0.70 (0.53–0.93) | 0.91 (0.68–1.21) | 0.84 (0.73–0.97) | 0.99 (0.76–1.29) |
| Stroke | 0.66 (0.35–1.25) | 0.26 (0.10–0.70) | 0.93 (0.72–1.20) | 0.91 (0.54–1.52) |
| CV death | 0.80 (0.44–1.44) | 0.84 (0.46–1.52) | 0.87 (0.73–1.05) | 1.14 (0.76–1.72) |
| Non-CV death | 1.51 (0.99–2.31) | 1.16 (0.64–2.10) | 0.97 (0.79–1.19) | – |
| All-cause death | 1.21 (0.86–1.71) | 0.98 (0.64–1.49) | 0.94 (0.83–1.06) | 1.16 (0.87–1.56) |
| LoDoCo2 | COLCOT | CANTOS | CIRT | |
|---|---|---|---|---|
| Trial design | Randomized, double-blind trial | Randomized, double-blind trial | Randomized, double-blind trial | Randomized, double-blind trial |
| Trial size | 5522 | 4745 | 10 061 | 4786 |
| Study population | Chronic coronary disease, clinically stable >6 months | MI within 30 days of enrolment | Previous MI and CRP ≥2 mg/L | Previous MI or multivessel coronary disease and type 2 diabetes or the metabolic syndrome |
| Active treatment | Colchicine 0.5 mg QD | Colchicine 0.5 mg QD | Canakinumab 50 mg, 150 mg, or 300 mg every third month | Methotrexate 15 or 20 mg OW and 1 mg of folate QD |
| Comparator | Placebo | Placebo | Placebo | Placebo and 1 mg folate QD |
| Primary endpoint definition | Composite of CV death, MI, ischaemic stroke, or ischaemia-driven coronary revascularization | Composite of CV death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization | Composite of CV death, non-fatal MI, non-fatal stroke | Composite of CV death, non-fatal MI, non-fatal stroke |
| Follow-up (median) | 29 months | 23 months | 3.7 years | 2.3 years |
| Age (years) | 66 | 61 | 61 | 66 |
| Female sex (%) | 15 | 19 | 25 | 19 |
| Diabetes (unspecified) (%) | 18 | 20 | 40 | 33 |
| Primary endpoint result | 0.69 (0.57–0.83) | 0.77 (0.61–0.96) | 0.88 (0.79–0.97) | 1.01 (0.82–1.25) |
| 3P-MACE* | 0.72 (0.57–0.92) | 0.85 (0.66–1.10)‡ | 0.88 (0.79–0.97) | 1.01 (0.82–1.25) |
| MI | 0.70 (0.53–0.93) | 0.91 (0.68–1.21) | 0.84 (0.73–0.97) | 0.99 (0.76–1.29) |
| Stroke | 0.66 (0.35–1.25) | 0.26 (0.10–0.70) | 0.93 (0.72–1.20) | 0.91 (0.54–1.52) |
| CV death | 0.80 (0.44–1.44) | 0.84 (0.46–1.52) | 0.87 (0.73–1.05) | 1.14 (0.76–1.72) |
| Non-CV death | 1.51 (0.99–2.31) | 1.16 (0.64–2.10) | 0.97 (0.79–1.19) | – |
| All-cause death | 1.21 (0.86–1.71) | 0.98 (0.64–1.49) | 0.94 (0.83–1.06) | 1.16 (0.87–1.56) |
Overview of CV outcome trials evaluating anti-inflammatory therapy. *3P-MACE defined as CV death, non-fatal MI, or non-fatal stroke. ‡Including resuscitated cardiac arrest. 3P, 3-point; CRP, C-reactive protein; CV, cardiovascular; MACE, major adverse CV event; MI, myocardial infarction; QD, once daily; OW, once weekly.
Mode of action of colchicine
Colchicine is an inexpensive pharmaceutical agent long used for the treatment of gout and familial Mediterranean fever.49 Colchicine acts at the cellular level by disrupting the cytoskeleton with inhibition of mitosis and intracellular transport by suppressing tubulin polymerization.49 In atherosclerosis and ASCVD, the anti-inflammatory properties of colchicine are seemingly exerted through inhibition of leucocyte recruitment to and activity in an inflamed area and inhibition of the NLRP-3 inflammasome (Figure 1).50In vitro experiments reported colchicine both reduced chemotaxis of neutrophils to an inflamed area,51 and reduced adhesion of leucocytes to inflamed endothelium.52–54 Colchicine accumulates in neutrophils due to their lack of P-glycoprotein that excretes colchicine from the intracellular to the extracellular space.55 Finally, colchicine has also been observed to inhibit the release of granular enzymes from neutrophils.56 Next to influencing neutrophils, colchicine influences macrophages with reduced secretion of tumour necrosis factor α, a pro-inflammatory cytokine, together with reduced expression of tumour necrosis factor α receptor on macrophages and endothelium.53,54 From in vivo observations, colchicine inhibits assembly and activation of the NLRP-3 inflammasome leading to indirect inhibition of downstream activation and reduced plasma levels of IL-1β, IL-6, and CRP.57,58 In addition to this inhibition of innate immunity, colchicine appears to suppress smooth muscle cell and myelofibroblast proliferation and fibrosis.59 Importantly, clinical data seem to corroborate these observations. Amongst 37 non-diabetic individuals with obesity and metabolic syndrome, colchicine 0.6 mg twice daily reduced circulating levels of CRP, IL-6, and markers related to neutrophil activity following 3 months of treatment as compared with placebo.60,61
Overview of mode of action of colchicine in type 1 diabetes. Red indicates influence on CV inflammation and green inflammation of the adipose tissue. Colchicine inhibits both leucocyte recruitment to and activity in an inflamed area, activation of the NLRP-3 inflammasome and secretion of TNF-α. Additionally, colchicine could be expected to influence insulin resistance due to low-grade inflammation in the adipose tissue in individuals with residual inflammatory risk, obesity, and type 1 diabetes. CRP, C-reactive protein; CV, cardiovascular; IL, interleukin; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3; TNF-α, tumour necrosis factor α.
In type 1 diabetes, we observed residual inflammatory risk, identified by a CRP ≥2 mg/L, to be associated with obesity and increased body fat mass, an atherogenic lipid profile, and elevated plasma levels of IL-6 and tumour necrosis factor α.12 In type 1 diabetes, obesity with insulin resistance may increase insulin requirements and consequently risk of hypoglycaemic episodes. From these observations, colchicine may influence not only cardiovascular inflammation but also modulate low-grade inflammation of the adipose tissue and insulin resistance in type 1 diabetes (Figure 1).
Colchicine reduces risk of major adverse cardiovascular events
Colchicine 0.5 mg administered once daily (QD) reduced risk of MACE in two CV outcome trials, even without enrichment of the study population with residual inflammatory risk (CRP ≥2 mg/L) as an inclusion criterion. In the Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease (LoDoCo2) trial, 0.5 mg colchicine QD reduced risk of MACE (composite of CV death, MI, ischaemic stroke, or ischaemia-driven coronary revascularization) by 31% (95% CI 0.57–0.83) as compared with placebo after median 28 months of treatment (Table 1).20 The study population consisted of persons with chronic coronary disease of whom 18% had diabetes and 5% were dependent on insulin therapy at baseline. In the Colchicine Cardiovascular Outcomes Trial (COLCOT), 0.5 mg colchicine QD reduced risk of MACE (composite of CV death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization) by 23% (95% CI 0.61–0.96) as compared with placebo after median 22 months of treatment (Table 1).19 Participants were persons with recent MI of whom 20% had diabetes at baseline. Importantly, in the LoDoCo2 trial, the observed CV benefits with colchicine appeared independently of time of treatment initiation with regard to previous MI,62 and they were sustained during the full 5 years of follow-up.63 A recent meta-analysis involving five studies (colchicine n = 5918; placebo or standard treatment n = 5898) put the relative risk reduction of MACE (MI, stroke, or CV death) with colchicine to 25% (95% CI 0.61–0.92).14 This composite outcome's individual subcomponents were reduced by 22% (95% CI 0.64–0.94) for MI, 46% (95% CI 0.34–0.86) for stroke, and for CV death numerically by 18% (95% CI 0.55–1.23) as compared with placebo, respectively.14 The 25% relative risk reduction of 3-point MACE with colchicine compares with risk reductions with blood pressure-lowering therapy,64,65 cholesterol-lowering therapy,66 and anti-thrombotic treatment.67–69 Relevant to type 1 diabetes, colchicine 0.5 mg QD was corroborated to reduce risk of MACE by 20% in persons with ASCVD and type 2 diabetes.70 Based on these results, colchicine was recently recommended for the treatment of residual CV risk in persons with existing ASCVD by the 2021 European Society of Cardiology (ESC) Guidelines on CVD prevention in clinical practice (class IIb recommendation and level A evidence).10 Additionally, colchicine 0.5 mg QD was approved by Health Canada in August 2021 for the reduction of atherothrombotic events in adult persons with existing coronary artery disease.71
Colchicine shows potential outside atherosclerotic cardiovascular disease
Colchicine treatment in CVD was recently expertly reviewed elsewhere, alluding to potential CV benefits with this anti-inflammatory agent not only in ASCVD but also in pericarditis and atrial fibrillation.50 In the treatment of acute and recurrent pericarditis, colchicine is recommended as first-line therapy (class 1 recommendation and level A evidence) in Europe by ESC.72 In the US, The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines suggest colchicine for pericarditis after MI (class IIb recommendation and level C evidence).73 These guidelines do not specifically mention individuals with diabetes but could also be applicable in type 1 diabetes, with adequate adjustment of insulin therapy in response to fever and the anti-inflammatory effects of colchicine. In the prevention of atrial fibrillation following cardiac surgery, ACC/AHA guidelines mention colchicine as a potential agent (class IIb recommendation and level B evidence)74; ESC notes colchicine is currently being investigated for the prevention of postoperative atrial fibrillation (NCT03310125).75 Diabetes is mentioned as a risk factor for developing atrial fibrillation,74 and recommendations involving colchicine ought to be applicable in type 1 diabetes. Looking toward the future, large randomized, clinical trials are ongoing evaluating treatment with colchicine in a range of potential indications including atrial fibrillation, acute coronary syndrome, and cerebrovascular disease.50
Safety considerations and drug interactions with colchicine
Colchicine has a narrow therapeutic index, with potential toxicity at overdose, but is administered at low-dose 0.5 mg QD for the treatment of ASCVD. For comparison, the recommended prophylactic treatment dose of gout is up to 1.2 mg daily.76 Colchicine is almost completely absorbed from the gastrointestinal tract, and it is primarily hepatically metabolized by cytochrome P450 3A4 (CYP3A4) and renally excreted by P-glycoprotein.77 Special care should be taken in patients with severe renal or hepatic insufficiency.78 Side effects include abdominal pain, nausea, vomiting, and diarrhoea. However, side effects have not been related to increased mortality or other organs like the liver, neuropathy, muscles, infection risk, or haematologic disturbances.79 In a recent meta-analysis of colchicine treatment in ASCVD, all-cause mortality was similar between groups but risk of non-CV death was numerically increased by 38% (95% CI 0.99–1.92) with colchicine as compared with placebo.14 No clear explanation was found for this trend in mortality, and it has to be further explored in more long-term follow-up studies.14 Importantly, long-term follow-up of colchicine therapy in a range of clinical conditions outside ASCVD have not reported this trend.79,80
Certain drugs increase the risk of colchicine toxicity by influencing the metabolism of colchicine through suppression of hepatic CYP3A4 enzymatic activity or renal efflux activity of P-glycoprotein. Strong inhibitors of CYP3A4 and P-glycoprotein should be avoided with colchicine therapy in patients with reduced liver or renal function (Table 2). Treatment with moderate CYP3A4 inhibitors should be carefully considered and treatment monitored (Table 2). Other potential drug interactions include 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors like atorvastatin, fluvastatin, pravastatin, and simvastatin; other lipid-lowering drugs like fibrates and gemfibrozil; and digitalis glycosides such as digoxin that is a P-glycoprotein substrate. Collectively, the safety of low-dose colchicine in type 1 diabetes must be corroborated in clinical trials, with adequate monitoring of the individual and taking into consideration relevant co-morbidities and concomitant medication.
Potential drug interactions influencing the metabolism and breakdown of colchicine
| Enzymatic pathway influenced | Drugs |
|---|---|
| Strong CYP3A4 inhibitors | Amprenavir, atazanavir, clarithromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, ritonavir, voriconazole |
| Moderate CYP3A4 inhibitors | Amiodaron, diltiazem, erythromycin, fluvoxamine, lopinavir, verapamil, grapefruit juice |
| Strong P-glycoprotein inhibitors | Ciclosporin, dronedarone, ketoconazole |
| Enzymatic pathway influenced | Drugs |
|---|---|
| Strong CYP3A4 inhibitors | Amprenavir, atazanavir, clarithromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, ritonavir, voriconazole |
| Moderate CYP3A4 inhibitors | Amiodaron, diltiazem, erythromycin, fluvoxamine, lopinavir, verapamil, grapefruit juice |
| Strong P-glycoprotein inhibitors | Ciclosporin, dronedarone, ketoconazole |
CYP3A4, Cytochrome P450 3A4.
Potential drug interactions influencing the metabolism and breakdown of colchicine
| Enzymatic pathway influenced | Drugs |
|---|---|
| Strong CYP3A4 inhibitors | Amprenavir, atazanavir, clarithromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, ritonavir, voriconazole |
| Moderate CYP3A4 inhibitors | Amiodaron, diltiazem, erythromycin, fluvoxamine, lopinavir, verapamil, grapefruit juice |
| Strong P-glycoprotein inhibitors | Ciclosporin, dronedarone, ketoconazole |
| Enzymatic pathway influenced | Drugs |
|---|---|
| Strong CYP3A4 inhibitors | Amprenavir, atazanavir, clarithromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, ritonavir, voriconazole |
| Moderate CYP3A4 inhibitors | Amiodaron, diltiazem, erythromycin, fluvoxamine, lopinavir, verapamil, grapefruit juice |
| Strong P-glycoprotein inhibitors | Ciclosporin, dronedarone, ketoconazole |
CYP3A4, Cytochrome P450 3A4.
Conclusions and future directions
Mounting evidence confirms both chronic systemic inflammation, coined as residual inflammatory risk, as an independent CV risk factor and that anti-inflammatory agents such as canakinumab and colchicine reduce risk of MACE in secondary prevention populations with coronary artery disease, including individuals with type 2 diabetes. Colchicine 0.5 mg QD for the prevention of ASCVD is a state-of-the-art therapy, and it is currently finding its way into international guidelines, and has so far been approved by Health Canada. Relevant to type 1 diabetes, colchicine 0.5 mg QD reduced risk of MACE by 20% in persons with type 2 diabetes.70 However, no data exist on how colchicine influences CV risk in type 1 diabetes, as such individuals are often excluded from CV outcome trials. Even though, similar CV benefits would be expected in type 1 diabetes, it is important to evaluate colchicine, specifically in this disease as to establish that the expected, beneficial anti-inflammatory effects are observed here and to evaluate any influence of colchicine on insulin therapy, including glycaemic control, and risk of hypoglycaemia. Clearly, it is essential to bridge this knowledge gap to facilitate the implementation of both chronic, systemic inflammation/residual inflammatory risk as independent CV risk factor and evaluate the efficacy and safety of colchicine on CV risk in type 1 diabetes. Future trials evaluating colchicine are warranted, optimally a CV outcome trial in type 1 diabetes. As such trials are unlikely to happen in the type 1 diabetes population, a well-designed phase 2 trial corroborating improvements in biomarkers of CV risk and indicating no adverse effects on insulin therapy may provide indirect evidence that the CV benefits of colchicine corroborated in CV outcomes trial outside diabetes may also be observed in this very high-risk population.
Acknowledgements
N.J.J. conceptualized the review, did the literature search, and wrote first draft of the manuscript. F.K.K. reviewed and edited the manuscript.
Conflict of interest: N.J.J. has received research support from JDRF, a travel grant from AstraZeneca, and has previously been employed by Novo Nordisk unrelated to the current work. F.K.K. has served on scientific advisory panels and/or been part of speaker's bureaus, served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi, ShouTi, Zealand Pharma, and Zucara.
Data availability
Not relevant.
