Inflammation mediates residual cardiovascular risk in statin-treated patients with coronary disease

This editorial refers to ‘Prognostic impact of residual inflammatory and triglyceride risk in statin-treated patients with well-controlled LDL cholesterol and atherosclerotic cardiovascular disease’, by F.M. Di Muro et al., https://doi.org/10.1093/eurjpc/zwaf112. Despite substantial progress in therapies aimed at reducing low-density lipoprotein (LDL) cholesterol, recurrent coronary events remain frequent. This residual risk is multifactorial and potential causes include (i) inflammation; (ii) elevated triglycerides; (iii) lipoprotein(a); (iv) remnant cholesterol, and (v) sub-optimally treated LDL-cholesterol, in addition to traditional risk factors. Identification of the most important mediators of residual cardiovascular risk may likely help in the prioritization of efforts in clinical practice and research. A large body of preclinical and clinical evidence has shown that inflammation is a critical contributor to atherogenesis. A key biomarker of inflammation, high-sensitivity C-reactive protein (hs-CRP), has been shown to predict better future cardiovascular outcomes than the lipid marker LDL-cholesterol in patients with atherosclerotic cardiovascular disease receiving statin therapy.1 Another readily measurable factor that may contribute to residual risk is plasma triglycerides. Evidence from multiple prospective cohorts and Mendelian randomization studies show that elevated triglyceride levels are associated with atherosclerotic cardiovascular disease.2 Triglyceride-rich lipoproteins appear to increase cardiovascular risk at least as much as LDL particles,3 and triglyceride levels above 150 mg/dL (1.7 mmol/L) are related to a 35% increase in subclinical non-coronary atherosclerosis independent of LDL-cholesterol.4 The relative value of the inflammation-related biomarker hs-CRP and plasma triglycerides in predicting future cardiovascular events in patients with established atherosclerotic cardiovascular disease already treated with a statin remains to be determined. In this issue of the European Journal of Preventive Cardiology, Di Muro et al.5 present the results of an observational single-center study examining the strength of the association of hs-CRP and triglycerides with future cardiovascular events in statin-treated patients with well-controlled LDL-cholesterol and known coronary artery disease. This real-world study included 9446 statin-treated patients, with LDL-cholesterol concentrations <70 mg/dL (<1.8 mmol/L), who underwent percutaneous coronary intervention (PCI) between 2012 and 2022. The investigators categorized participants according to their hs-CRP and fasting triglyceride levels measured before PCI. Those with hs-CRP <2 mg/L and triglycerides <150 mg/dL (<1.7 mmol/L) were taken as the reference group. Elevated hs-CRP alone (≥2 mg/L) was labelled residual inflammatory risk, elevated triglycerides alone (≥150 mg/dL) was termed residual triglyceride risk, and high levels of both hs-CRP (≥2 mg/L) and triglycerides (≥150 mg/dL) were considered residual combined triglyceride and inflammatory risk. The authors then examined whether elevated hs-CRP alone, elevated triglycerides alone, or the combination predicted higher cardiovascular event rates. The primary endpoint of the study was the 1-year incidence of major adverse cardiovascular events (MACE), defined as the composite of all-cause mortality, myocardial infarction, or stroke. Nearly 38% of patients exhibited residual inflammatory risk (hs-CRP ≥2 mg/L), indicating that persistent inflammation is common among statin-treated patients with adequately controlled LDL-cholesterol. In this population, presence of elevated triglycerides (≥150 mg/dL) was much less common (approximately 12%). After adjusting for multiple variables, individuals with residual inflammatory risk had a significantly higher incidence of MACE (hazard ratio: 1.82, 95% CI: 1.42–2.33, P < 0.001) compared to the reference group. The finding was consistent in both patients with acute and chronic coronary syndromes, which is in line with the benefits of the anti-inflammatory medication colchicine in both settings.6,7 The heightened MACE risk in the residual inflammatory group was driven predominantly by all-cause mortality. This finding aligns with a previous analysis showing that hs-CRP predicts not only cardiovascular events but also mortality.1 In contrast, individuals with only residual triglyceride risk had outcomes that were not significantly different from those of the reference group (hazard ratio: 1.37, 95% CI: 0.85–2.20, P = 0.19). However, the numbers of patients and clinical events in the elevated TG only group were small. Similarly, a comparison of the group of residual combined inflammatory and triglyceride risk with that of residual inflammatory risk alone would have lacked statistical power. Although LDL-cholesterol reduction is the cornerstone of cardiovascular prevention, patients remain exposed to substantial residual cardiovascular risk. This has created the impetus for the development of complementary preventive approaches. Inflammation reduction with low-dose colchicine has been shown to reduce safely the risk of cardiovascular events in the COLCOT and LoDoCo2 trials in more than 10 000 patients with coronary artery disease followed for approximately 2 years.6,7 Despite the important flaws of CLEAR-SYNERGY including the major under-reporting of myocardial infarction due to the COVID-19 pandemic and the inadequate control of inflammation,8 the addition of that study in the most recent meta-analysis of long-term trials of colchicine in approximately 22 000 patients showed statistically and clinically significant reductions of at least 25% in MACE, myocardial infarction, stroke, and urgent coronary revascularization.9 Although elevated triglycerides have been associated with cardiovascular events, recent randomized trials have produced inconsistent findings. In the REDUCE-IT trial, icosapent ethyl improved cardiovascular outcomes but the effect was not related to the baseline level of triglycerides or their change over time.10 In contrast, the PROMINENT trial did not show a significant effect on cardiovascular risk of pemafibrate-mediated triglyceride lowering.11 An important limitation of the current study was its short follow-up of patients, which was limited to 1 year. Nevertheless, the study demonstrated once more that inflammation is common in patients with atherosclerotic disease and is strongly associated with future cardiovascular events and mortality despite statin therapy.1 These results are in line with the robust reduction in cardiovascular events with low-dose colchicine in the most recent systematic review and meta-analysis of long-term trials.9 Accordingly, colchicine 0.5 mg once daily has been approved by the United States Food and Drug Administration to reduce the risk of myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease. Colchicine was also given a class IIa recommendation in the recent European Society of Cardiology guidelines for the treatment of patients with coronary artery disease.12 Indeed, physicians should no longer consider intensive lipid lowering and inflammation reduction as mutually exclusive but rather as complementary approaches in statin-treated patients with atherosclerotic cardiovascular disease. The quest to reduce further residual risk continues, and addressing inflammation represents a critical step in preventing cardiovascular events. V.M. drafted the manuscript. J.-C.T. critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy. Dr V.M. is personally supported by the Sigrid Jusélius and Orion Research Foundation. No specific grant from any funding agency in the public, commercial, or not-for-profit sectors was received for the conduct of this study. No new data were generated or analysed in support of this editorial.

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