Abstract
Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.
Highlights
Inflammation has been implicated in the pathobiology of cardiovascular disease,[1,2] but it is unclear whether inflammation is a direct cause of disease or a marker of disease response
Prospective cohort studies have shown that markers of inflammation, such as C-reactive protein (CRP)[3] and interleukin-64,5 (IL-6), are positively associated with an increased risk of cardiovascular events, and studies employing Mendelian randomization have suggested that the association between IL-6 and risk may be causal.[6]
Prospective studies have shown that low-density lipoprotein cholesterol (LDL-C) is positively associated with risk of major vascular events,[7,8] while randomized trials of statins[9] have shown that lowering LDL-C reduces cardiovascular risk, confirming that LDL-C is a cause of atherosclerotic disease
Summary
Inflammation has been implicated in the pathobiology of cardiovascular disease,[1,2] but it is unclear whether inflammation is a direct cause of disease or a marker of disease response. Prospective cohort studies have shown that markers of inflammation, such as C-reactive protein (CRP)[3] and interleukin-64,5 (IL-6), are positively associated with an increased risk of cardiovascular events, and studies employing Mendelian randomization have suggested that the association between IL-6 and risk may be causal.[6] Prospective studies have shown that low-density lipoprotein cholesterol (LDL-C) is positively associated with risk of major vascular events,[7,8] while randomized trials of statins[9] (and, more recently, of proprotein convertase subtilisin/kexin type 9 or PCSK-9 inhibitors10) have shown that lowering LDL-C reduces cardiovascular risk, confirming that LDL-C is a cause of atherosclerotic disease It is unclear whether the presence of inflammation influences the relationship between LDL-C and cardiovascular disease. This affords the opportunity to examine: (i) the association of CRP with risk of cardiovascular disease; (ii) the associations, in randomized and observational analyses, of LDL-C with risk of cardiovascular disease; (iii) whether the degree of underlying inflammation modified the strength of the association between LDL-C and cardiovascular risk in this population; and (iv) the separate associations of CRP and of LDL-C with nonvascular outcomes
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