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Low-density lipoprotein cholesterol: How low do we go, and how do we do it?

ESC Congress News 2015 - London

THE LDL HYPOTHESIS refers to the concept that excess low density lipoprotein (LDL) cholesterol causes arteriosclerotic cardiovascular disease. This hypothesis is based on animal and epidemiological data, and is also supported by monogenic disorders like familial hypercholesterolemia. As with every causal factor, the last step to prove causality is the reversal of disease incidence progression by the reversal of the risk factor.

Risk Factors and Prevention

By Heinz Drexel,  Academic Teaching Hospital, Feldkirch, AustriaThere is strong evidence that, with progressive LDL-cholesterol lowering, a progressive reduction in atherosclerotic cardiovascular events can be achieved. Seminal knowledge has been provided by the Cholesterol Treatment Trialists Collaborators (CTTC) who first reported in 2005 that a reduction by 1 mmol/l of LDL-cholesterol exerts a consistent 23% reduction in risk for major coronary events over five years. This first meta-analysis was followed by one on diabetes, one on intensive statin treatment and one on primary prevention and women, which all corroborated the LDL hypothesis.    

Because all the studies included in the CTTC meta-analysis were statin trials, an alternative hypothesis, the ‘statin hypothesis’, was promoted, in which a speculation of non-LDL-effects, the so called pleiotropic effects as a cause for endpoint reduction, was raised. Based on the uncertainty of the cause-effect relationship, the joint AHA/ACC guidelines recommended use of statins and not to try to achieve target levels. This appeared appropriate because no other trial evidence existed for non-statin lipid lowering drugs being effective to lower the incidence of endpoints.    

Earlier this year important new evidence in favour of the LDL-hypothesis was obtained, which will be described at an Advances in Science symposium later this morning. In the IMPROVE-IT trial the non-statin substance ezetimibe, given in addition to simvastatin and with simvastatin plus placebo as the comparator, showed improved benefit when lowering the LDL-cholesterol to 1.4 mmol/l versus 1.8 mmol/l in the comparator group. Importantly, the amount of event rate reduction with the additional ezetimibe was exactly the same as predicted in the CTTC statin meta-analysis (see Figure).     

Hence, this study became a strong argument in favour of the LDL-hypothesis: i) even lower is even better and ii) a non-statin drug exerts the same magnitude of effect as could be expected from an equally effective statin. This further lowering of LDL-cholesterol was without additional adverse events. All these data point to the fact that the scientific community has probably not overstated the LDL hypothesis - that ‘the lower, the better’.    

IMPROVE-IT trial data – Change in LDL-cholesterol versus clinical benefit (from Cannon CP et al. NEJM 2015; 372: 2387-2397).

This is an important basis for newer additional ways of reducing LDL-cholesterol by the monoclonal antibodies against PCSK9. These molecules can reduce LDL-cholesterol to even lower levels than those achieved by simvastatin plus ezetimibe.    

Today’s session on ‘Low-density lipoprotein cholesterol: how low and how to lower?’ will focus on the target and on the tools to reach the target. In this context it should not be forgotten that many studies worldwide, like the European/Canadian DYSIS-study, have shown that adherence to statins is much lower than desired. About 7% of patients discontinue statins per year, giving many clinicians the opinion that, besides asking ‘how low and how to lower’, the main question remains ‘how to lower the discontinuation rate’.    

This is encouraging for the ESC and its guidelines on lipid lowering, which include targets for LDL-cholesterol – in contrast to American guidelines, which target the tool but not the level achieved. Probably the ‘ESC way’ to treatment targets is the best of the possible approaches.


Low-density lipoprotein cholesterol: how low and how to lower? 29 Aug 11:00-12:30 San Marino - Village 2