Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have become important agents in lipid-lowering therapy to reduce atherosclerotic cardiovascular disease (ASCVD) risk. Targeting the intrahepatic lysosomal degradation of low-density lipoprotein (LDL) receptors, these therapies increase hepatic expression of LDL receptors and are efficacious in lowering circulating LDL cholesterol (LDL-C) by ~60%. In 2015, based on data from the ODYSSEY LONG TERM (Long-term Safety and Tolerability of Alirocumab [SAR236553/REGN727] Versus Placebo on Top of Lipid-Modifying Therapy in High Cardiovascular Risk Patients With Hypercholesterolemia), OSLER-1 (Open-Label Study of Long-Term Evaluation against LDL Cholesterol) and OSLER-2 trials, the National Lipid Association (NLA) released recommendations for the use of PCSK9 inhibitors, noting that PCSK9 inhibitors should be considered in 1) patients with ASCVD who have LDL-C ≥100mg/dL while on maximally tolerated statin ± ezetimibe therapy, and 2) in those with heterozygous familial hypercholesterolemia (FH) while on maximally tolerated statin ± ezetimibe therapy.¹

In 2017, the NLA released updated recommendations on the use of PCSK9 inhibitors, using more recent and well-executed clinical trials, in particular GLAGOV (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound) and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), to guide recommendations.² They provide explicit recommendations for use of PCSK9 inhibitors in 1) stable ASCVD; 2) progressive ASCVD; 3) FH/LDL-C ≥190 mg/dL; and 4) very high-risk patients with statin intolerance.

GLAGOV was a trial that randomized patients to receive monthly subcutaneous injections of evolocumab 420mg or placebo. Patients were ≥18 years of age with at least one coronary artery stenosis of ≥20% and a target vessel suitable for imaging with ≤50% stenosis with LDL-C ≥60 or 80 mg/dL depending on the risk factor profile on stable lipid-lowering therapy.³ In the group treated with evolocumab, LDL-C level was 37 mg/dL at the end of the 76-week treatment period, compared to 93 mg/dL in the placebo group. The percent atheroma volume decreased by 0.95% in the evolocumab group and was unchanged in the placebo group (p < 0.001). Prior evidence suggests that a percent atheroma volume reduction of 0.5% is clinically significant.

FOURIER randomized patients with ASCVD and LDL-C ≥70 mg/dL on maximally tolerated statin therapy to receive evolocumab or placebo.⁴ At 48 weeks, evolocumab significantly reduced the risk of the primary endpoint, a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, with a number needed to treat of 67 over two years. A sub-study of FOURIER further showed no significant difference in cognitive function between evolocumab and placebo after a mean of 19 months (EBBINGHAUS [Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in High cardiovascUlar Risk Subjects] trial). Based on these high-quality trials, the NLA recommends consideration of PCSK9 inhibitors for ASCVD risk reduction in patients with stable ASCVD, particularly those on maximally-tolerated statin therapy ± ezetimibe with on-treatment LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL (strength A, quality high). Further, in those with progressive ASCVD and similar statin/ezetimibe therapy and LDL-C/non-HDL-C values, PCSK9 inhibitors can also be considered (strength B, quality moderate).

Regarding the FH phenotype with pretreatment LDL-C ≥190 mg/dL, PCSK9 inhibitors may be used to reduce LDL-C in these patients, although recommendations vary slightly based on age with those ages 40 and 79 having the strongest recommendation strength and quality. While there are no dedicated ASCVD outcomes data on use of PCSK9 inhibitors in this group, both evolocumab and alirocumab have been shown to significantly reduce LDL-C.^5,6 Given the ASCVD risk reduction in FOURIER was compatible with that expected per mmol/L or mg/dL lowering of LDL-C based on CTT Collaboration data, there is reason to believe that FH patients will derive even greater benefit from PCSK9 inhibitors.

Lastly, high-risk patients with statin intolerance as defined by the NLA Statin Expert Panel who require additional lipid-lowering therapies may benefit from PCSK9 inhibitors, as supported by the GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects -3) trial.^7,8 Statin intolerance is defined as the inability to tolerate a statin dose that is sufficient to reduce a person's cardiovascular risk and can result from a variety of side effects including muscle symptoms, nausea, headache, sleep disorders, and dyspepsia, among others.⁹ Further, there are two different clinical patterns: complete intolerance and partial intolerance. Complete intolerance refers to intolerance of a statin at any dose, whereas partial intolerance refers to intolerance of some statins at some doses.¹⁰

The GAUSS-3 trial randomized patients who were unable to tolerate an effective statin dose to either evolocumab versus ezetimibe, using an atorvastatin-controlled crossover phase to objectively identify statin intolerance.⁸ During the crossover phase, 27% had muscle symptoms on placebo but not statin while 43% had muscle symptoms on statin but not placebo. Of those who had statin intolerance on the basis of having muscle symptoms only on atorvastatin, mean percent change in LDL-C levels at 24 weeks were -16.7% with ezetimibe versus -52.8% with evolocumab. Nearly 29% of ezetimibe-treated patients and 21% of evolocumab-treated patients reported muscle symptoms, with 5 of 73 ezetimibe-treated patients requiring discontinuation of the study drug and 1 of 145 evolocumab-treated patients requiring discontinuation of the study drug.

The NLA recommendations help guide clinicians as they begin to consider PCSK9 inhibitor therapy and, given the novelty of the therapy, shared decision-making is important when determining whether to initiate a PCSK9 inhibitor. The issues of cost and difficulty in accessing therapy through insurance coverage are very important to discuss.

PCSK9 Inhibitors Have a Role in the Treatment of Stable and Progressive ASCVD

The results of both GLAGOV and FOURIER support the utility of PCSK9 inhibitors in treatment of stable and progressive ASCVD, particularly when lifestyle modification and maximally-tolerated statin therapy have been prescribed and LDL-C remains ≥70 mg/dL; 73.5 million adults in the United States have elevated LDL-C but less than half receive treatment and only one-third have LDL-C levels in the desired range.^11,12 For patients who are not at target LDL-C goals despite statin therapy, PCSK9 inhibitors offer an additional therapeutic option. It is also important to consider the role of ezetimibe in LDL-C lowering therapy, which lowers LDL-C by ~20% when used alone.¹³ If ezetimibe is not already prescribed and the goal LDL-C is greater than 25% reduction, then proceeding to PCSK9 inhibitor may be appropriate. However, in patients who are close to their LDL-C goal on maximally-tolerated therapy but not ezetimibe, the next step may be initiation of ezetimibe prior to considering PCSK9 inhibitor therapy, since we have solid clinical outcomes data with the (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial).

PCSK9 Inhibitors Are Important Considerations in Statin Intolerance

Statin intolerance, as defined above, is a phenomenon which affects up to 15% of patients who are treated with statins.⁹ This represents a very large number of adults when you take into account the impact of elevated LDL-C on ASCVD, importantly the increased ASCVD risk in statin-intolerant patients with known ASCVD. However, it is important to distinguish between complete and partial statin intolerance. Importantly, patients who report an adverse event in the setting of a statin may be able to continue statin therapy and ultimately reduce their risk of cardiovascular disease, a finding highlighted in a recent study by Zhang and colleagues.¹⁴ In this retrospective cohort study, patients who reported an adverse event in the setting of statin therapy and who were subsequently continued on statin therapy had decreased incidence of cardiovascular events (myocardial infarction, stroke, or death) compared to those who did not continue a statin (12.2% vs. 13.9%). However, ~27% of patients who reported an initial adverse reaction to statin and were initiated on a different statin had a second adverse event. Although statin intolerance is a real phenomenon that affects many patients, there can be additional adverse events with discontinuation of statin therapy and thoughtful discussions between patients and providers should focus on determination of partial versus complete statin intolerance and the harm of discontinuing statin therapy, particularly in those with partial intolerance.¹⁵

For patients with complete statin intolerance, non-statin therapies may be the most appropriate option. Until recently, non-statin therapies have included medications such as ezetimibe which, as described above, may not lower LDL-C levels to the desired range. In very high-risk patients with statin intolerance who require substantial additional cholesterol lowering therapy despite non-statin therapies already in place, the addition of PCSK9 inhibitors may be beneficial to lower LDL-C levels and prevent progression of ASCVD. Although the NLA recommendations list the strength of this recommendation as C and the quality low, the advent of PCSK9 inhibitors offer an additional lipid-lowering therapy that this vulnerable population may benefit from, and is an important consideration in shared-decision making. The official FDA label is for use of PCSK9 inhibitors on top of maximally-tolerated statin therapy, and in some patients no statin may be the maximally-tolerated statin.

The Importance of Shared Decision Making in Initiating PCSK9 Inhibitor Therapy

Shared decision making is the cornerstone of medical practice and the pinnacle of patient-centered care. In considering whether to initiate PCSK9 inhibitor therapy, there must be a thoughtful discussion between the patient and provider regarding the risks and benefits. Consideration of number needed to treat to benefit the patient, cost, and need for subcutaneous injections are important factors to discuss, along with patient beliefs and preferences. Regarding the number needed to treat, it is important to realize that as an absolute risk measure this depends on the time horizon; the number over 10 years is expected to be significantly lower than over 2 or 5 years. Although the current annual cost of PCSK9 inhibitor therapy is approximately $14,000,¹⁶ these are important therapies that need to be seriously considered for certain patient populations. There is valid frustration with barriers to access to PCSK9 inhibitors from both providers and patients, including the extensive paperwork and substantial time investment required for prior authorization.¹⁷ Shared decision making coupled with efforts to lift barriers to access will help ensure that patients who may benefit from PCSK9 inhibitor therapy are well-informed and well-treated.

Summary

The NLA recommendations provide important, evidence-based guidelines as PCSK9 inhibitors begin to be used more frequently as lipid-lowering therapies in the above conditions. PCSK9 inhibitors have clear benefits in treatment of stable and progressive ASCVD but generic ezetimibe and more intensive lifestyle changes should generally be considered before starting a PCSK9 inhibitor. Moreover, given the non-trivial number of patients who experience statin intolerance, PCSK9 inhibitors offer an additional treatment option. Lastly, the decision to pursue PCSK9 inhibitor therapy needs to be approached as a thoughtful discussion between provider and patient that considers risks, benefits, and patient preferences.

References

1. Jacobson TA, Maki KC, Orringer CE, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol 2015;9:S1-122.
2. Orringer CE, Jacobson TA, Saseen JJ, et al. Update on the use of PCSK9 inhibitors in adults: recommendations from an expert panel of the National Lipid Association. J Clin Lipidol 2017. [Epub ahead of print]
3. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patietns: the GLAGOV randomized clinical trial. JAMA 2016;316:2373-84.
4. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
5. Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015;36:2996-3003.
6. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:331-40.
7. McKenney JM, Davidson MH, Jacobson TA, Guyton JR, National Lipid Association Statin Safety Assessment Task Force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97:89C-94C.
8. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA 2016;315:1580-90.
9. Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. Position paper from the International Lipid Expert Panel. Arch Med Sci 2015;11:1-23.
10. Mancini GB, Tashakkor AY, Baker S, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can J Cardiol 2013;29:1553-68.
11. Johnson NB, Hayes LD, Brown K, Hoo EC, Ethier KA, Centers for Disease Control and Prevention. CDC National Health Report: leading causes of morbidity and mortality and associated behavioral risk and protective factors--United States, 2005-2013. MMWR Suppl 2014;63:3-27.
12. Mozaffarian D, Benjamin EN, Go AS, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 2016;133:e38-360.
13. Battaggia A, Donzelli A, Font M, Molteni D, Galvano A. Clinical efficacy and safety of ezetimibe on major cardiovascular endpoints: systematic review and meta-analysis of randomized controlled trials. PLoS One 2015;10:e0124587.
14. Zhang H, Plutzky J, Shubina M, Turchin A. Continued statin prescriptions after adverse reactions and patient outcomes: a cohort study. Ann Intern Med 2017. [Epub ahead of print]
15. Nissen SE. Statin denial: an internet-driven cult with deadly consequences. Ann Intern Med 2017. [Epub ahead of print]
16. Arrieta A, Page TF, Veledar E, Nasir K. Economic evaluation of PCSK9 inhibitors in reducing cardiovascular risk from health system and private payer perspectives. PLoS One 2017;12:e0169761.
17. Baum SJ, Toth PP, Underberg JA, Jellinger P, Ross J, Wilemon K. PCSK9 inhibitor access barriers-issues and recommendations: improving the access process for patients, clinicians and payers. Clin Cardiol 2017;40:243-54.

Keywords: Cholesterol, LDL, Hypercholesterolemia, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Hyperlipoproteinemia Type II, Receptors, LDL, Plaque, Atherosclerotic, Risk Factors, Cardiovascular Diseases, Constriction, Pathologic, Dyspepsia, Antibodies, Monoclonal, Angina, Unstable, Atherosclerosis, Myocardial Infarction, Antibodies, Monoclonal, Angina, Unstable, Atherosclerosis, Stroke, Coronary Stenosis, Risk Reduction Behavior, Injections, Subcutaneous, Nausea, Life Style, Dyslipidemias

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