Statins continue to be the drug of choice for LDL-C therapy, although not all patients achieve their target levels with therapy alone. However, the paradigm shift implemented in the new American guidelines is controversially discussed among Swiss experts.
Prof. von Eckstein, at the end of last year, the new guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA) on cholesterol therapy were published. What has changed?
Prof. Dr. med. von Eckardstein:
The guidelines represent a paradigm shift. LDL cholesterol target values were removed and patients were divided into four groups – so-called “statin benefit groups”. For the different groups, the professional societies make therapy recommendations of varying intensity. For patients with clinically manifest atherosclerosis or patients at high cardiovascular risk, treatment with intensely active statins – atorvastatin or rosuvastatin – is provided with the goal of a 50% reduction in LDL cholesterol levels. This change is the subject of controversial debate in Switzerland. Not only because the previous strategy with absolute target values for LDL cholesterol has proven itself well and is widely accepted. The second change concerns risk calculation. In the United States, if this algorithm had been used, at least 60% of adult white males would have had to be treated with statins. Without recalibration, almost all men in Switzerland would require treatment.
Since the CTT meta-analysis, it is known that there is a linear relationship between LDL reduction and decrease in cardiovascular events. Is there a threshold above which this effect is no longer detectable?
We know that the more we reduce LDL-C, the lower the cardiovascular event rate. Whether this correlation is no longer detectable at some point and where the threshold value lies has not yet been investigated. However, you have to think about how far you want to go in lowering LDL. As the dose increases, one accepts the risk of potential side effects with a concomitant decrease in benefit.
A Spanish observational study has shown that affected individuals who – despite having normal LDL-C levels – were treated with statins following ACS benefited from significantly lower all-cause and cardiovascular mortality. How do you assess these results?
This question leads us to discuss whether the effect of statins is due to the lowering of LDL-C alone, or whether the much discussed pleiotropic effects of statins, such as an anti-inflammatory effect, also play a role. Personally, I believe the effect is due to the lowering of atherogenic LDL-C.
The maximum LDL cholesterol reduction that can be achieved with statin therapy alone is about 50%. In which patients do you recommend the additional use of a cholesterol absorption inhibitor?
In principle, therapy with the cholesterol absorption inhibitor ezetimibe can be considered in all patients in whom the target LDL value is not achieved with a potent statin such as rosuvastatin or atorvastatin. Ezetimibe results in an additional decrease in LDL-C of up to 20% and a small increase in HDL-C. We do not know whether the additional LDL-C reduction is associated with a decrease in cardiovascular risk. Initial information on clinical endpoints will be provided by the IMPROVE-IT study, the results of which are expected at the end of this year.
Following the premature termination of two trials of niacin and the cholesterol ester transfer protein (CETP) inhibitor torcetrapib to raise HDL levels, the HDL hypothesis has begun to wobble. Is there any news in this area?
The HDL hypothesis has been repeatedly challenged. However, part of the problem stems from the fact that we are not able to determine actual HDL. The HDL-C we measure in the blood is a surrogate marker that only provides information about the cholesterol bound to HDL. However, HDL consists of different subtypes that differ not only in size and composition, but also in their effects.
As for the trials, I think the question of niacin treatment became moot after the AIM-HIGH and HPS2-THRIVE trials were stopped. Not much can be said yet about the development of CETP inhibitors. Studies of evacetrapib and anacetrapib have shown promising HDL-C increase and LDL-C reduction in safety studies. The impact of these changes on cardiovascular outcomes is currently under investigation.
The monoclonal antibody PCSK9 was found to be a promising and very potent compound for LDL lowering. What is the state of research in this area and for which patients might the MAH be suitable one day?
The development of therapeutic antibodies that inhibit PCSK9 began about ten years ago when so-called gain-of-function mutations in the PCSK9 gene were found to cause autosomal dominant hypercholesterolemia in French patients and loss-of-function mutations in the PCSK9 gene were found to cause low LDL cholesterol and greatly reduced risk of myocardial infarction, primarily in African Americans. Initial studies show that the antibodies lead to a significant LDL reduction of 60%. However, it is unclear whether these result in the hoped-for cardiovascular risk reduction. The current studies were primarily concerned with testing safety. Phase III studies evaluating efficacy on cardiovascular endpoints have been initiated.
A recent Gulf Registry data analysis shows that women have worse outcomes after ACS than men due to treatment differences. Treatment differences also exist in Switzerland, as data from the AMIS diabetes treatment registry show. Do differences exist in lipid treatment recommendations for women or when do the same criteria apply?
Treatment disparities between women and men are a reality. However, the problem is increasingly being noticed, so some improvements have been made in this area. We now know that women have at least are just as likely to suffer from cardiovascular diseases, but these occur later. As for secondary prevention, the same treatment recommendations apply to women and men. Primary prevention, on the other hand, is more difficult. The current risk assessment, which calculates the 10-year risk of a fatal cardiovascular event, is suboptimal for women. With the calculation of long-term risk, as newly recommended by the International Atherosclerosis Society and discussed by the American cardiology societies, this will change. Then a statin will also be used earlier in women.
Interview: Regina Scharf
CARDIOVASC 2014; 13(2): 31-32
