C. Richard Conti, MD, MACC

Introduction

There is now a new way to treat hypercholesterolemia, using a monoclonal antibody (Evolocumab)that binds to and inhibits PCSKA 9. Most physicians know the term PCSK 9 but have no idea what PCSK9 stands for (including me). My purpose for writing this editorial is to educate myself on what PCSK 9 is and what it does. My hope is that I can perhaps educate those reading this document as well.

Present Ways to Reduce Cholesterol Levels

In addition to life style modification, practically everyone knows the enzyme HMG CoA reductase inhibitors, (Statins) decrease morbidity and mortality from coronary heart disease by decreasing LDL[1]. Hardly anybody know what PCSK 9 is and what PCSK 9 inhibitors do to decrease cholesterol levels. PCSK 9 is an enzyme called Proprotein convertace subtilisin/Kexin type 9. This substance is a bad actor since it binds to the low density lipoprotein receptor, decreasing the number of LDL receptors to bind to LDL, which increases the LDL.

Blocking PCSK 9 with PCSK 9 antibodies (Evolocumab) decreases blood LDL by 59%because it allows more LDL receptors to be available to bind to LDL and thereby lower serum LDL concentration.

A Recent Clinical Trial of PCSK 9 Inhibition

The clinical trial, “Fourier” was presented at the American College of Cardiology annual scientific session in 2017.The rationale for any clinical trial of a PCSK 9 inhibitor is that if you lower cholesterol you will decrease the risk of subsequent coronary heart disease. This is a legitimate hypothesis but a question arises related to the lowest level of serum cholesterol, i.e. what should be our target.Someone said that “you cannot be too rich or too thin”. Steve Nissen, in a commentary about this question added to the quote that ‘’you cannot have too low a cholesterol”.

It may be the PCSK 9 inhibitors can be used in patients who are “statin intorerant,” but this was not tested, in the Fourier trial. It must be remembered that this trial was performed on a background of Statin therapy and there are no data, yet available,to indicate that this drug should be used in patients who are Statin intolerant. The Fourier clinical trial of Evolocumab [2], trade name Repatha was performed in patients with an LDL＞70 mgm/dL and clinical evidence for coronary heart disease or vascular disease.

“Fourier” was a randomized, double-blind, placebo controlled, multinational trial. Amgen and the TIMI study group at Brigham and Women’s Hospital in Boston designed the trial. In 49 countries, twenty seven thousand five hundred and sixty four patients were randomized to either evolocumab or placebo.Median duration of follow-up was 26 months.

All patients were taking an optimized regimen of lipid lowering therapy with or without ezetimibe.The primary end point was major cardiovascular events defined as a composite of death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization.

Results of Fourier: Efficacy and Safety

Efficacy

The primary outcome of Fourier, occurred in 9.8%of the treatment group and 11.3% in the placebo group, an absolute difference of 1.5%. This was statistically significant but a few are concerned that the result may not be clinically relevant since the cost of this product is so high (at the moment, the cost is approximately $14,000 per year).

There was a 21% relative risk reduction for stroke and a 27% relative risk reduction for heart attack.There was no effect on cardiovascular mortality,but the duration of follow-up is too short to detect a mortality benefit in patients with known coronary or vascular disease.

The investigators indicated that 74 patients would need to be treated over a period of 2 years to prevent one cardiovascular death, myocardial infarction or stroke.

Safety

Safety was not a concern, since the rates of adverse events were no different in the treatment group than in the placebo group. However, since the study was a relatively short duration study, it is not known what will happen to these patients in 10–20 years relating to safety. The investigators will be following a cohort of patients and will provide observational data on safety as well as efficacy.

Cost Concerns

The cost of this drug on a yearly basis at the moment is rather high but as with most other drugs,the cost will probably decrease as years progress,particularly if the manufacturer wants it to be used in hypercholesterolemic patients other than the very high risk of familial hypercholesterolemic patients or the patient who is statin intolerant.

Conclusion

The key question that arises is “is the incremental benefit with PCSK 9 inhibition worth it to reduce the adverse cardiac events in patients already on cholesterol lowering drugs at this cost.” The investigators and many other think it is. Time will tell！

REFERENCES

1. Wong WD. ACC/AHA guidelines for cardiovascular disease prevention and cholesterol management:implications of new therapeutic agents. Cardiovasc Innov Appl 2016;1(4):399–408.

2. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD,Murphy SA, et al. Evolocumab, and clinical outcomes in patients with cardiovascular disease. NEJM 2017.DOI: 10.1056/NEJMoa1615664(e-publication).