Lipids Lowdown From ESC: PCSK9 Inhibitors and LDL-C Goals

Michelle L. O'Donoghue, MD, MPH; M. John Chapman, PhD, DSc


October 14, 2014

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Buzzing About PCSK9 Inhibitors

Michelle L. O'Donoghue, MD: My name is Michelle O'Donoghue. I have with me John Chapman, who is a leading expert in prevention as well as dyslipidemia. We are coming to you from the European Society of Cardiology (ESC) Congress in Barcelona.

M. John Chapman, PhD, DSc: It has been a tremendously exciting ESC Congress, particularly with the advent of highly efficacious monoclonal antibodies to PCSK9 and low-density lipoprotein cholesterol (LDL-C) lowering, with the first event data, which are very promising. We live in exciting times.

Dr O'Donoghue: You are touching on what everyone wants to talk about right now—the PCSK9 inhibitors—and the level of enthusiasm that people have for this new class of compounds that lead to very aggressive LDL-C reduction.

Dr Chapman: The PCSK9 inhibitors are promising, not only in individuals with high LDL-C levels, with what we call non-familial hypercholesterolemia (FH). These are individuals whose genes for the LDL receptor appear normal. In FH, the patients have at least one defective gene that is involved in the breakdown of cholesterol carried in LDL and they respond equally well. Typically these antibodies achieve approximately a 60% reduction in LDL-C, even in patients with the most severe forms of FH, with LDL-C levels of 400-500 mg/dL, in whom both alleles coding for the LDL receptor gene are affected.[1,2,3] The most recent results[4] with evolocumab indicate that we can get up to 30% reduction in LDL-C levels. When combined with a statin and potentially with an inhibitor of cholesterol absorption and a resin, we can start to approach—even in those most severe patients—the LDL-C targets that have been recommended in the ESC/European Atherosclerosis Society (EAS) guidelines.[5,6]

LDL-C Goals vs Risk Reduction

Dr O'Donoghue: You hit on the important issue of LDL targets, which are obviously very controversial right now in light of the new guidelines. Should we be targeting actual numbers for LDL-C reduction? Is this about relative risk reduction or just about being on a lipid-lowering therapy?

Dr Chapman: This is a critically important question, and it has taken on new life within the past few months since the new US recommendations[7] appeared. New DNA sequencing technology, particularly in The Netherlands and Denmark (and to a lesser degree in two or three other countries in Europe), indicates that the frequency of FH is twice as high as we ever imagined, on a calculated basis for the past 50 years. The frequency of FH is 1 in 230 individuals, which means that 39-40 million people around the world are affected.[8]

We know that the risk for premature major events in FH can be up to 15 times higher because of the elevated LDL-C. In our clinic we typically see individuals for clinical atherosclerotic vascular disease who are approaching the end of their first decade of life. If we treat these patients according to risk only with a one-shot treatment (eg, statins, potentially in combination with another agent) and we don't follow up with those patients and we don't respect a goal, then the question that can be raised is: Are we bringing the maximum clinical benefit to those patients?

My response is, we are not. We absolutely need to aim for those LDL-C goals from the ESC/EAS, bringing LDL-C down to 100 mg/dL (2.5 mmol/L) in individuals at high risk and patients with FH whose LDL levels are > 200 mg/dL (5 mmol/L). In very high-risk individuals, the target is 70 mg/dL (1.7 mmol/L). Across Europe we feel quite strongly that goals are exceedingly useful to clinicians and are even more important for high- and very high-risk patients.

Time to Target Lp(a)?

Dr O'Donoghue: Your comments about goals are interesting because there has been a lot of discussion about the PCSK9 inhibitors and the fact that they lower lipoprotein a [Lp(a)] levels; we certainly don't have a lot of therapies that are effective in lowering Lp(a). Statins have a variable effect on Lp(a) and some statins even raise those levels a little bit.

Should physicians be starting to think about Lp(a) as a secondary target or is that premature? Do we know whether Lp(a) is causal in the atherogenic pathway?

Dr Chapman: In the EAS consensus publication in the European Heart Journal[6] in 2011, for the first time we drew attention through the work of an international panel of experts to the very important risk associated with levels of Lp(a) above the 80th percentile (> 50 mg/dL or > 200 nmol/L).

The interest in Lp(a) has increased because there are now Mendelian randomization studies that clearly identify it as a causal factor in the pathophysiologic pathway of atherosclerosis. Moreover, Lp(a) has been implicated in premature aortic stenosis and it seems to stabilize the plaque by at least partially inhibiting the fibrinolytic process.

You might say that Lp(a) is a criminal who wears several hats. That appears to be the case. The effects of statins are very irregular, if they have any effect at all. Niacin, which is available in the United States, leads to a significant reduction (up to 30%).[9] The PCSK9 monoclonal antibodies reduce circulating Lp(a) levels by 30%-35%. Of greatest importance, cumulative data from the evolocumab program, published in the past year, suggest that we can consistently—independently of the baseline level—reduce Lp(a) levels by 30%.[10]

The genotype of the apo(a) protein does not appear to be a factor in determining response to these monoclonal antibodies, so the recommendation made by the EAS consensus paper was that in high-risk patients (those who present with incident coronary, or atherosclerotic vascular disease) there should be a systematic assay determination of Lp(a), because it increases the risk associated with elevated LDL levels about 1.5 times. The genome-wide association study data are consistent with Lp(a) as a major lipid risk factor.

Dr O'Donoghue: One of the more exciting things that came out of the Congress was a signal that PCSK9 inhibitors may lead to a lower risk for cardiovascular events, although very few events were seen in this cohort. It is still encouraging overall.[11] Would you agree on that point?

Dr Chapman: As we discussed in the Cardiology Show with Dr Valentin Fuster, one of the most poignant aspects of those studies is that the curves for composite cardiovascular endpoints appear to separate as early as 3-4 weeks following introduction of this monoclonal antibody treatment targeted to PCSK9, with dramatic LDL-C reductions of 60%. It is exceedingly encouraging.

Use in Statin Intolerant or Everyone?

Dr O'Donoghue: You have given a lot of thought to patients who are statin intolerant and whether the prevalence is as high as has been stated in the past. Do you view the PCSK9 inhibitors as being an alternative therapy for patients who are statin intolerant, or do you think these therapies will be used for all patients who are not at goal?

Dr Chapman: At the moment, the greatest challenge that we have by far is in the population of patients with FH, which is estimated to affect 39 million worldwide. The main challenge is the recognition of the disease by clinicians, the diagnosis of those high LDL-C levels, and the introduction of an effective therapy.

We are aware that there is a real phenomenon of so-called "statin intolerance," which primarily manifests itself as a form or diverse forms of muscular symptomatology. It appears to be real, and from the very recent EAS consensus panel and data from Paul Thompson in the United States in the STOMP study,[12] we seem to be looking at a frequency of approximately 5%. Very frequently, it appears to be related to genetic factors, which translate ultimately into an attenuated ability of mitochondria in muscle to produce energy.

We are making major headway in our understanding of that muscular symptomatology and moving away from the psychosomatic consideration of what, for many clinicians, has always been associated with the statin-intolerance phenomenon.

Dr O'Donoghue: It is such an important area of exploration so it is good to hear that many promising advances are being made. Thank you for joining me today. I think it has been a very exciting Congress, and the lipid field is all abuzz right now with the PCSK9 class.


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