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Kendrick asks...should we care about C-reactive protein?

A surprising new study has suggested statins could reduce the risk of CV disease in people with normal lipids but high CRP levels. Our clinical columnist Dr Malcolm Kendrick takes a hard look at the evidence.

A surprising new study has suggested statins could reduce the risk of CV disease in people with normal lipids but high CRP levels. Our clinical columnist Dr Malcolm Kendrick takes a hard look at the evidence.

The recently published JUPITER study looked at people with low LDL but elevated ‘high-sensitivity' C-reactive protein levels. It was found that rosuvastatin ‘significantly reduced the incidence of major cardiovascular events, despite the fact that nearly all study participants had lipid levels at baseline that were well below the threshold for treatment according to current prevention guidelines1' (my italics).

The study – once again – rekindles the issue of risk factors for disease, and how to establish if they are causal or merely associations. CRP is a relatively non-specific marker of inflammation, produced by the liver. It can be raised in inflammatory conditions such as RA, and in people with increased visceral fat. It is also raised in people at increased risk of CVD.

So the central question this study raises is: were the beneficial effects of rosuvastatin due to the lowering of CRP – which was reduced by 37% – or to other effects that both lowered CRP and reduced CVD risk at the same time?

Fascinatingly, the entire issue of CRP and atherosclerosis was the subject of a major Danish study that was analysed and discussed in the New England Journal of Medicine only two weeks before that same journal published the JUPITER study2,3.

The purpose of the Danish study was to ask if CRP is a causal factor in CVD. The key findings ‘strongly indicate that CRP is not causally involved in the pathogenesis of atherosclerotic disease. Thus, immediate targeting of CRP is unlikely to be beneficial in reducing the risk of cardiovascular events'.

But just two weeks later the JUPITER study was published, looking at the effect of rosuvastatin on people with raised CRP levels – finding that CV events and CRP levels were significantly reduced. As the authors noted: ‘Given the recognition that atherothrombosis is in some respects a disorder of innate immunity, we hope the data presented here spur the further development of anti-inflammatory drugs as potential vascular therapeutic agents.'

But anti-inflammatory agents like diclofenac appear to significantly increase the risk of CVD. The example of rofecoxib (Vioxx) further strengthens the idea that anti-inflammatories may worsen the risk of CVD. And of course, steroids – the most powerful anti-inflammatory agent we can prescribe – significantly increase the risk of CVD.

Inflammation, after all, is the body's natural reaction to injury. By reducing inflammation, we may be impairing the ability of the body to heal itself.

So, where does this leave CRP? Is it just a marker of inflammation in the body, or a cause of CVD? Should we rush to develop specific CRP lowering agents?

Cautionary tale

An example from near history warns us against this approach. It has long been recognised that low levels of HDL cholesterol are very strongly associated with an increased risk of CVD. It was considered by almost everyone involved in cardiovascular research that HDL cholesterol was not merely a marker of a metabolic problem but was protective – removing cholesterol from atherosclerotic plaques and transporting it back to the liver. Working on this hypothesis, Pfizer started a major trial of torcetrapib, an agent that both increased HDL levels and lowered LDL levels. But this trial was stopped prematurely in 2006, after it was noted that those taking the drug had a 60% increase in cardiovascular events and overall mortality.

It remains a possibility that CRP is a modifiable causal factor for CVD but I think that seems unlikely. A rush to find CRP-lowering agents could backfire, as with HDL. For it is theoretically possible that using anti-inflammatories, or CRP-lowering agents, may hamper the body's own repair mechanisms.

I suggest that the most likely explanation for statins reducing the risk of CVD in people with higher CRP is that statins are having an underlying effect, such as increased nitric oxide synthesis, which protects the endothelium from damage. Reducing endothelial damage protects against plaque rupture and thrombotic events on arterial walls. This in turn reduces inflammation, and the CRP level falls. After all, the body does not inflame first and damage second. The process is damage followed by repair and inflammation – and raised CRP levels are an indication of this.

So an agent that reduces CRP levels is very unlikely to have a beneficial effect, on anything. So, does CRP matter? Is it a causal factor for CVD? Probably not. It is most likely just a marker of underlying damage.

Dr Malcolm Kendrick is a GP in south Manchester

Dr Malcolm Kendrick

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