Atherosclerosis is an inflammatory disease (1). Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing atherosclerotic cardiovascular disease (2). Patients with chronic coronary artery disease (CAD) who also have diabetes mellitus are particularly at high risk for recurrent cardiovascular events, which underscores the need for new therapeutic options (3).

T2DM is a multifactorial disease characterized by insulin resistance and relative insulin deficiency attributed to islet beta-cell failure causing hyperglycemia and dyslipidemia (4). Obesity is a low-grade chronic inflammatory disease and is the most crucial factor in the development of T2DM and related metabolic disorders (5, 6). Therefore, the role of inflammation in general and oligomerization of nucleotide-binding domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in particular on the onset and progression of T2DM has been hypothesized (7, 8). Small studies suggest that therapy that targets the inflammatory cytokine interleukin-1 (IL-1) can improve glycemic control in T2DM (9, 10). However, in the larger substudy of the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), targeting interleukin-1β (IL-1β) did not result in better glycemic control or a reduction in the incidence of new-onset T2DM (11).

The Colchicine Cardiovascular Outcomes Trial (COLCOT) and Low-Dose Colchicine 2 (LoDoCo2) trial demonstrated that low-dose colchicine reduces the risk for cardiovascular death, myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization in unselected patients with recent myocardial infarction and chronic CAD, respectively (12, 13). Colchicine has broad anti-inflammatory effects that include inhibition of the NLRP3 inflammasome and polymerization of tubulin that affects leukocyte function (14–16). In this study, we assessed the efficacy of colchicine on cardiovascular events and the effect of colchicine on the development of new-onset T2DM in patients with chronic CAD with and without diabetes mellitus (17).

The LoDoCo2 trial (ACTRN12614000093684) was a double-blind randomized clinical trial, with a total of 5,522 patients randomized to colchicine 0.5 mg (n = 2,762) or placebo once daily (n = 2,760). Recruitment started in 13 centers in Western Australia in 2014 and was expanded to 30 centers in the Netherlands in 2016. Enrollment ended in 2018. The median follow-up time was 28.6 months (interquartile range, 20.5–44.4). The patients were eligible if they were aged 35–82 years, had established chronic CAD, were clinically stable for at least 6 months prior to randomization, and were able to tolerate colchicine during a 30-day run-in period. Randomization was performed in a double-blind 1:1 fashion to colchicine or placebo that was performed by a computerized algorithm. The primary efficacy endpoint was composed of major adverse cardiovascular events (MACE+), namely, cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven revascularization. Secondary endpoints consisted of the aforementioned events, separately. The endpoints were revised several times before unblinding of the data. All cardiovascular events were judged by a clinical events committee blinded to treatment allocation.

Calculation of the sample size for the original trial has previously been published and details can be found in the study protocol (12, 18). To summarize, with 5,447 randomized participants, the study would achieve a beta of <0.10 at a two-sided alpha of 0.05 to detect a difference of 30% in the incidence of the primary composite endpoint between treatment groups. Diabetes status and insulin treatment were assessed at the time of randomization. A participant who was not on diabetes treatment at the time of randomization and subsequently started treatment was defined as having “new-onset T2DM.” The trial protocol was approved by a centralized institutional review board in each participating country (MEC-U, Nieuwegein, Netherlands; and Sir Charles Gairdner Group HREC, Perth, Australia). All patients provided written informed consent. Additional details of the design, statistical analyses, baseline characteristics of the participants, and primary results of LoDoCo2 have been published (12, 18).

This LoDoCo2 substudy confirms that patients with chronic CAD who also have T2DM are at higher risk of MACE than patients without T2DM. It also demonstrates that colchicine produces consistent benefits in preventing recurrent MACE in patients with and without T2DM. While the incidence of new-onset T2DM in the colchicine group was numerically lower, this difference was not statistically significant.

The hypothesized underlying role of inflammation in T2DM relates to the belief that obesity results in the recruitment of macrophages into the adipose tissue and subsequent induction of a pro-inflammatory environment, which contributes to insulin resistance (20–22). Concomitant relative islet beta-cell dysfunction attributed to either inflammation or genetic predisposition results in insulin deficiency and further propels hyperglycemia contributing to the development or progression of T2DM (21–25). Therapy with IL-1 and IL-1β antibodies specifically targets these cytokines mediated by the NLRP3 inflammasome, whereas colchicine directly attenuates the inflammasome (26, 27). Also, the mechanisms of actions of colchicine reach beyond the IL-1 pathway (15, 28). Therefore, a wider therapeutic effect could be expected from colchicine, but we were unable to demonstrate this.

The effects of anti-inflammatory therapy on cardiovascular events had also been assessed in the pre-specified DM substudy of CANTOS. The study showed that the beneficial effect of the IL-1β inhibitor canakinumab in patients with a baseline high-sensitivity C-reactive protein of ≥2 mg/L and history of MI did not differ between participants with and without T2DM (11, 29). The current LoDoCo2 substudy adds to the accumulating evidence confirming the consistent reduction of the composite primary endpoint by the anti-inflammatory drug colchicine, independent of T2DM status. Because patients with DM are at higher risk of adverse cardiovascular events, they can be expected to derive greater absolute benefits from colchicine than patients without DM. This was also recently hypothesized in patients with type 1 diabetes (30).

The effects of anti-IL-1 therapy on glycemic control have also been studied in patients with T2DM. A study on the use of anti-IL-1 therapy in patients with rheumatoid arthritis and T2DM reported improved glycemic control (9). A clinical trial in 70 patients with an IL-1-receptor antagonist in T2DM improved glycemic control and reduced inflammation, although these findings have not been confirmed (10, 31). In CANTOS, the HbA1c values were not affected by IL-1β inhibition (11). This could not be explored in the LoDoCo2 study because glycemic control was not measured.

The effect of anti-inflammatories on the incidence of new-onset T2DM was only prospectively studied in CANTOS, showing no treatment difference between the treatment and placebo groups (11). For colchicine, two retrospective cohort studies compared new-onset T2DM in patients treated with colchicine or without colchicine for gout. Both studies showed a reduction in new-onset T2DM in the colchicine population, compared with the findings of the present study (32–34). The numerical lower rate of new-onset T2DM in the present study is consistent with the hypothesis that anti-inflammatory therapy by using colchicine possibly prevents or delays new-onset T2DM, although low numbers preclude any definitive conclusions. Statins also have anti-inflammatory properties, but meta-analyses have suggested an increase in the risk of new-onset T2DM with statins (34–36). This raises the possibility that different (inflammatory) pathways are involved in new-onset DM and the development of atherosclerosis.

Many currently available therapies for T2DM have anti-inflammatory properties, but it is not known whether their anti-inflammatory effects are beneficial (37). Several ongoing trials are investigating the role of anti-inflammatory therapy in patients with CAD and diabetes, such as the ZEUS trial with ziltivekimab (NCT05021835) and the CLEAR SYNERGY trial with colchicine (NCT03048825).