Statins reduce cholesterol-levels and have the ability to reduce heart disease risk. However, some researchers have asked if the primary mode of action of statins is cholesterol reduction. After all, statins have several effects in the body which might reduce the risk of heart disease in ways that have essentially nothing to do with cholesterol. For example, statins enhance nitric oxide production (this helps dilate blood vessels), have anti-inflammatory effects (see below), and also have the ability to reduce clotting in the blood (e.g. reduced fibrinogen levels and inhibition of platelet adhesion and aggregation).
Today saw the publication of a study which reinforced this idea. It involved the treatment of individuals deemed to be at high risk of cardiovascular disease with a statin (simvastatin) or placebo [1]. This research was designed to assess whether the effect of statin therapy was in any way influenced by levels of a substance known as C-reactive protein (CRP) in the body. CRP is a marker of inflammation, and inflammation is a key underlying process in heart disease. Statins are anti-inflammatory. Could it be, therefore, that statins work between in individuals with raised CRP levels. In short, this study found that risk reduction was essentially the same across different levels of CRP. In other words, in the study, CRP levels did not appear to help identify individuals who might benefit most from statin therapy.
But an interesting finding from this study, I think, is the fact that statin therapy appeared to reduce cardiovascular events (such as heart attack and stroke) in individuals with low LDL-cholesterol (supposedly ‘unhealthy’) levels. Now, low levels of cholesterol are not a risk factor for cardiovascular disease. So, if statins broadly help individuals with low LDL levels, that does suggest their main mode or modes of action here do not relate to cholesterol reduction.
This is not, however, the first time research has found statins reduce cardiovascular disease risk in individuals with ‘normal’ or even ‘low’ cholesterol levels [2]. It is also interesting to note that statins substantially reduce the risk of stroke, despite the fact that raised cholesterol levels are a weak or non-existent risk factor for stroke [3,4]. Also, more intensive cholesterol reduction does not necessarily lead to improved outcomes [5].
All of this also calls into question the wisdom of cholesterol reduction generally. If cholesterol reduction does indeed have broad benefits for health, we would expect to see positive effects from cholesterol-reducing strategies in terms of risk of total mortality. However, in a meta-analysis (pooling together of several similar studies) of a variety of cholesterol-reducing strategies including drug treatments [6], neither fibrates nor resins (two forms of cholesterol-reducing drugs) were found to reduce overall mortality. In fact, in this meta-analysis, other than statins, no cholesterol-reducing strategy analysed was found to reduce overall mortality.
Some argue that other cholesterol-reducing strategies fail to reduce cholesterol enough compared to statins. However, in this meta-analysis statin therapy was found to reduce cholesterol by 20 per cent on average, and this was associated with reduced mortality. This level of cholesterol reduction was matched by resin therapy in those with a prior history of cardiovascular disease, yet there was no reduction in overall mortality here.
In 2002, a new type of cholesterol-reducing drug – ezetimibe – was licensed for use. The basis for this decision was ezetimibe’s proven cholesterol-reducing effect. However, to date, no studies have been published which show that this agent has the capacity to reduce CVD risk or mortality.
Moreover, one trial found that treatment with ezetimibe actually increased thickening in the wall of the arteries (carotid artery intima thickness). Most importantly, ezetimibe use was associated with five times the risk of cardiovascular events (e.g. heart attacks, stroke) compared to another treatment (niacin – a form of vitamin B3) [7]. Such findings clearly call into question the view that cholesterol reduction, through whatever means, is beneficial to cardiovascular and general health.
The reason that this is important is because that we are generally encouraged to drive our cholesterol levels to ever-lower levels, and there is good evidence which questions the fundamental assumptions on which this approach is based. Research suggests that cholesterol reduction, per se, does not have broad benefits for health. Though I do admit the drugs companies and the researchers in their pay have done a generally very good job of persuading us otherwise.
References:
1. Heart Protection Study Collaborative Group. C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20 536 patients in the Heart Protection Study. The Lancet, Early Online Publication, 28 January 2011
2. Ridker PM, et al, JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195-2207
3. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet 1995;346(8991-8992):1647-53.
4. Imamura T, et al. LDL cholesterol and the development of stroke subtypes and coronary heart disease in a general Japanese population: the Hisayama study. Stroke 2009;40(2):382-8
5. Kastelein JJ, et al, ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358(14):1431-1443
6. Studer M, et al. Effect of different antilipidemic agents and diets on mortality: a systematic review. Arch Intern Med 2005;165(7):725-30
7. Taylor AJ, et al. Extended-Release Niacin or Ezetimibe and Carotid Intima–Media Thickness. N Engl J Med 2009; 361:2113-2122]
