Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation

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.

Keywords: C-reactive protein; LDL cholesterol; inflammation; randomized trials; vascular disease.

Figure 1

Association between usual C-reactive protein (CRP) and the risk of (a) major vascular events and (b) nonvascular events, and the association between usual low-density lipoprotein cholesterol (LDL-C) and the risk of (c) major vascular events and (d) nonvascular events. Hazard ratios (HRs) adjusted for age, sex, ethnicity, treatment allocation, prior diabetes, prior vascular disease, smoking, body mass index, high-density lipoprotein cholesterol, and renal status are noted (above squares), along with numbers of events (below squares). Average HR (95% confidence interval [CI]) throughout the range of values studied (i.e., assuming a log-linear relationship for LDL−C and a log-log-linear relationship for CRP), corresponding to about 1 SD difference in the usual LDL−C/log CRP.

Figure 2

Effect of allocation to simvastatin plus ezetimibe on (a) major vascular events and (b) nonvascular events by level of C-reactive protein. CI, confidence interval; LDL-C, low-density lipoprotein cholesterol.