Inflammation Drives Residual Risk in Chronic Kidney Disease

A CANTOS Substudy

Paul M. Ridker; Katherine R. Tuttle; Vlado Perkovic; Peter Libby; Jean G. MacFadyen

Disclosures

Eur Heart J. 2022;43(46):4832-4844. 

In This Article

Abstract and Introduction

Abstract

Aims: Hyperlipidaemia and inflammation jointly contribute to atherosclerotic disease. Yet, after the initiation of statin therapy, the relative contributions of these processes may differ in patient groups, such as those with and without impaired kidney function.

Methods and Results: Among 9151 stable statin-treated post-myocardial infarction patients participating in the CANTOS trial, the contributions of residual cholesterol risk and residual inflammatory risk were evaluated as determinants of recurrent major adverse cardiovascular events (MACE) and total mortality, stratified by baseline estimated glomerular filtration rate (eGFR) above or below 60 mL/min/1.73 m2 using the race agnostic CKD-EPI 2021 formula (all participants had eGFR > 30 mL/min/1.73 m2). Analyses of residual inflammatory risk focused on high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) while analyses of residual cholesterol risk focused on LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C). Participants were followed for a period of up to 5 years (median 3.7 years). Median baseline levels of LDL-C and hsCRP were 81 mg/dL and 4.2 mg/L. Among participants with eGFR ≥ 60 mL/min/1.73 m2, increasing quartiles of plasma hsCRP, IL-6, LDL-C, and non-HDL-C all positively associated with risks of recurrent MACE [hazard ratios (HR) comparing the top to bottom quartile for hsCRP 1.45; for IL-6 2.48; for LDL-C 1.64; and for non-HDL-C 1.68] (all P < 0.0001). By contrast, among those with eGFR < 60 mL/min/1.73 m2, increasing quartiles of hsCRP and IL-6 significantly predicted recurrent MACE [HR comparing the top to bottom quartile for hsCRP 1.50 (P = 0.021); for IL-6 1.84 (P = 0.048)], whereas increasing quartiles of LDL-C and non-HDL-C did not [HR comparing the top to bottom quartile for LDL-C 1.04 (P = 0.80); for non-HDL-C 0.98 (P = 0.88)]. The predictive utility of hsCRP and IL-6 in the setting of eGFR < 60 mL/min/1.73 m2 remained significant after adjustment for a wide range of potential confounding factors including age, sex, smoking status, blood pressure, body mass index, and diabetes. For the endpoint of total mortality, both hsCRP (HR 1.77, P = 0.0021) and IL-6 (HR 2.15, P = 0.015) were significant predictors among those with eGFR < 60 mL/min/1.73 m2, whereas LDL-C (HR 0.91, P = 0.56) and non-HDL-C (HR 0.85, P = 0.31) were not. Similar effects were observed in analyses stratified by the albumin to creatinine ratio rather than eGFR.

Conclusion: Among atherosclerosis patients with impaired kidney function already aggressively treated with statin therapy, residual inflammatory risk plays a substantial role in determining the risk of recurrent cardiovascular events. These data have implications for risk stratification of individuals with chronic kidney disease and for the development of novel agents that target inflammatory processes in this high-risk group of patients.

Clinical Trial Registration: ClinicalTrials.gov: NCT01327846

Structured Graphical Abstract

Among atherosclerosis patients with impaired kidney function already aggressively treated with statin therapy, residual inflammatory risk plays a substantial role in determining the risk of recurrent cardiovascular events. As shown, in the setting of chronic kidney disease, inflammation drives residual major adverse cardiovascular event risk more than LDL cholesterol.

Introduction

Hyperlipidaemia and inflammation jointly contribute to the development of atherosclerosis such that following statin therapy, additional lipid lowering, as well as additional inflammation inhibition have proven effective in further reduction of cardiovascular risk in major randomized trials.[1–5] On the basis of these trial data, the concepts of 'residual cholesterol risk' and 'residual inflammatory risk' for patients already taking statin therapy have taken on importance for physicians addressing the secondary prevention of atherothrombotic events.[6]

In specific statin-treated populations, the relative contributions of hyperlipidaemia and inflammation may vary. One clinically important group is individuals with atherosclerosis and chronic kidney disease (CKD) who have particularly high risk for recurrent vascular events despite aggressive lipid lowering. In this group, inflammation in the NLRP3 to interleukin (IL)-1 to IL-6 pathway of innate immunity is hypothesized to be a strong mediator of both atherosclerotic disease and progression of CKD.[7,8] Thus, potential differences in the relative importance of residual cholesterol risk and residual inflammatory risk after initiation of statin therapy among those with and without kidney impairment could have relevance for cardiovascular risk stratification and for the selection of potential therapeutic options. As one example, the benefit of sodium–glucose cotransporter 2 (SGLT2) inhibitors[9,10] and glucagon-like peptide-1 receptor agonists[11,12] in the setting of CKD and diabetes may result, in part, to anti-inflammatory effects of these agents.[13,14]

To address these issues in a contemporary cohort, the relative utility of lipid and inflammatory biomarker levels were evaluated as predictors of future major adverse cardiovascular events (MACE), cardiovascular mortality, and all-cause mortality in a group 9151 stable statin-treated post-myocardial infarction patients participating in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), stratified by estimated glomerular filtration (eGFR) rates <60 or ≥60 mL/min/1.73 m2 (all CANTOS participants had baseline eGFR > 30 mL/min/1.73 m2). The primary analyses focused on LDL-cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) with secondary analyses focused on non-high-density lipoprotein cholesterol (non-HDL-C) and IL-6. Additional secondary analyses stratified participants on the albumin to creatinine ratio (ACR) <3 or ≥3 mg/mmoL, rather than on eGFR.

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