Commentary on Residual inflammatory risk: lessons from trials for the future

Residual cardiovascular risk is multifactorial. Beyond cholesterol, seminal trials have demonstrated the clinical benefit of targeting residual inflammatory risk in high risk patients with well controlled LDL cholesterol levels. This latest commentary discusses evidence from these trials and future therapeutic approaches to residual inflammatory risk.

Residual inflammatory risk: lessons from trials for the future

Low-density lipoprotein cholesterol is indisputably causal for atherosclerotic cardiovascular disease (ASCVD) (1), and therapeutic approaches that lower this modifiable risk factor, including statins, PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors and ezetimibe, reduce cardiovascular events (2,3). Indeed, lowering low-density lipoprotein cholesterol (LDL-C) as much as possible is a key premise of the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) dyslipidaemia guidelines (4). Yet even with attainment of very low LDL-C levels with highly efficacious combination therapy, high and very high-risk patients continue to experience cardiovascular events. This underlines the need to target other contributors to cardiovascular risk, beyond the established modifiable risk factors.

Atherosclerosis is a chronic inflammatory process, initiated by macrophage release of proinflammatory mediators that promote leukocyte recruitment and transmigration to the subendothelial space, leading to plaque progression. Activation of macrophages and T-cell lymphocytes within the plaque perpetuates a local inflammatory response (5). Thus, as vascular inflammation is a driver of the risk of recurrent atherothrombotic events, it is logical to consider targeting residual inflammatory risk. This residual risk is common even in people with well controlled LDL-C levels. For example, among ASCVD patients with LDL C levels <1.8 mmol/L (<70 mg/dL) in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial), and SPIRE-1/SPIRE-2 (Studies of PCSK9 Inhibition and the Reduction of Vascular Events-1 and -2), about one-third had residual inflammatory risk, as defined by a high-sensitivity C-reactive protein (hsCRP) value ≥2 mg/L (6). Even at very low LDL-C levels (<0.5 mmol/L or <20 mg/dL), patients with higher hsCRP levels were at greater absolute cardiovascular risk. In FOURIER (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), 3-year event rates for the key secondary endpoint (a composite of myocardial infarction [MI], stroke, or cardiovascular death) were 13.1% for those with hsCRP levels >3 mg/L versus 9.0% for those with levels <1 mg/dL (7). Similar findings were reported in ASCVD patients in real-world clinical practice, including those undergoing coronary intervention (8,9).

Targeting key inflammatory pathways and their downstream mediators is a logical strategy to reduce residual inflammatory risk. Two key studies have provided evidence for proof of this concept: CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) (10) and COLCOT (Colchicine Cardiovascular Outcomes Trial) (11). In CANTOS, the target for therapeutic intervention was interleukin (IL)-1β, which plays a key role in driving atherosclerosis, while at the same time avoiding effects on immune function. In MI patients with well controlled LDL-C levels (mean 2.1 mmol/L or 82 mg/dL) but with residual inflammatory risk (median hsCRP 4.2 mg/L), treatment with canakinumab, a fully human IL-1β neutralizing monoclonal antibody administered 150 mg every 3 months, resulted in a significant 15% reduction in major cardiovascular events versus placebo (10). There was greater clinical benefit with more pronounced reduction in hsCRP (12). Treatment with generally safe and well tolerated; although there was a slightly higher rate of death due to infection or sepsis versus placebo, there was no increase in opportunistic infections (10). While canakinumab is not available as a therapeutic option, these landmark findings have been critical in driving the search for other IL-1β inhibitors.

In COLCOT, the therapeutic intervention was colchicine. Although this agent is traditionally used to treat gout, there is also evidence of anti-inflammatory effects, mediated by interference with several functions of leucocytes and the assembly of the NOD-like receptor protein 3 (NLRP3) inflammasome and release of IL-1β (13). In patients with a recent acute MI, treatment with colchicine 0.5 mg daily led to a significantly lower risk (by 23%) of the primary endpoint, a composite of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalisation for angina leading to coronary revascularisation, compared with placebo (11).

As in the arena of lipid clinical trials, however, there have been disappointments, most notably CIRT (Cardiovascular Inflammation Reduction Trial). CIRT investigated the potential of low-dose methotrexate in patients with a previous MI or multivessel coronary disease who also had either type 2 diabetes or the metabolic syndrome. This trial was terminated early on the recommendation of the data and safety monitoring board due to futility (14). The lack of benefit with methotrexate may be partly explained by patient selection issues. Whereas CANTOS specifically targeted patients with residual inflammatory risk (hsCRP levels ≥2 mg/L) (10), this was not the case for CIRT, in fact median hsCRP at baseline was 1.5 mg/L (14). Therefore, as evident in lipid trials, for example contrasting baseline triglycerides in REDUCE-IT versus ACCORD Lipid (15,16), patient selection matters.

Where to in the future?

Consideration of the target is pertinent to future development. Evidence from CANTOS and COLCOT suggests that intervening within the NLRP3 inflammasome:IL-1:IL-6 pathway shows promise. Beyond new inhibitors of IL 1β, there is interest in the therapeutic potential of small molecule inhibitors of the NLRP3 inflammasome. Increased understanding of the structure of the NLRP3 inflammasome and its individual components has aided the synthesis of rationally designed small molecule NLRP3 inflammasome inhibitors (17).

Added to this, recent analyses from CANTOS show that even after inhibition of IL-1β with canakinumab, there is substantial residual inflammatory risk which is related to IL-18 and IL-6. After 3 months on canakinumab, each tertile increase in on-treatment levels of IL-18 was associated with a 15% increase in the risk of major adverse cardiovascular events. The increase in risk was even higher for IL-6, with each tertile increase in on-treatment levels of IL-6 associated with a 42% increase in risk (18). These findings suggest that direct targeting of IL-6 signalling may merit investigation.

The stage is set for personalised biomarker-based therapeutic approaches offering new possibilities for reducing residual inflammatory risk that persists in ASCVD patients with well controlled LDL-C levels.


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