From the NLA President: Newly Published Guidance for Non-Statin Therapies from the American College of Cardiology

In April 2016, an expert consensus decision pathway on the role of non-statin therapies for lowering LDL-C in the management of atherosclerotic cardiovascular disease (ASCVD) risk was published in the Journal of the American College of Cardiology. This document, which was endorsed by the National Lipid Association (NLA), and with the diligent and consistent work of our Immediate

Past President Carl Orringer, MD, as one of its authors, provides practical guidance for clinicians and patients in situations that were not covered by the joint 2013 American College of Cardiology/ American Heart Association (ACC/AHA) guidelines. The need for such a document was emphasized by recent additions to the body of knowledge for risk factor reduction in cardiovascular disease. Since the publication of the last guidelines, the Food and Drug Administration has approved a new class of medications termed proprotein convertase subtillisin/kexin 9 or, most often referred to as, PCSK9 inhibitors for high-risk patients who may require additional therapies to bring the LDL-C to a more acceptable threshold. The recent results of the HPS2-THRIVE and IMPROVE-IT trials have also provided new data that provided new evidence with regard to the addition of second non- statin agents when additional lowering is warranted.

The publication of these new guidelines are in concert with the standards and recommendations made by the NLA, and we are excited to endorse the work of the initial “think tank,” which resulted in this publication. We are further pleased to report that Dr. Orringer has accepted the invitation of the ACC committee when it convenes this Fall in Washington, DC, as it moves its work forward assessing and making recommendations for barriers around implementation of evidence-based LDL-C lowering therapies for ASCVD reduction. We are grateful for the ongoing energy that he brings to this work and look forward to outcomes from this meeting.

Algorithms found within the current document provide a suggested clinical workflow for consideration of additional non-statin therapies. Ten points were specifically highlighted to assist the provider to fully understand and implement its recommendations.

1.  The decision pathway was created to address GAPS in recommendations for LDL-C lowering to reduce ASCVD in high-risk subsets based on recent clinical trial evidence and the introduction of a new class of lipid- lowering medication

2.  The 2013 ACC/AHA cholesterol guidelines identified four major statin benefit groups, which remain intact and include:

a.    Patients > 21 with clinical ASCVD

b.    Adults > 21 years of age with LDL-C > 190 mg/dL (after ruling out secondary causes)

c.    Adults 40–75 years old without known ASCVD but with diabetes, with LDL-C 70-189 mg/dL

d.    Adults 40–75 years without ASCVD or diabetes, with an LDL-C 70–189 mg/dL, and an estimated 10-year risk for ASCVD of > 7.5 percent, as determined by the pooled cohort equations.

3.  The 2013 guidelines recommended using either high- or moderate- intensity statin therapy for primary and secondary prevention, with dose adjustments as identified for adverse effects, elderly population, comorbidities, or drug-drug interaction.

4.  The evidence-based recommendations from the 2013 guidelines provided the framework for the newest guideline and incorporated the most recent clinical trial data and the newly approved PCSK9 inhibitors.

5.  Three questions were utilized to provide more detailed recommendations for specific patient scenarios.

a.    In what patient populations should non-statin therapies be considered?

b.    In what situations should non- statin therapies be considered?

c.    If non-statin therapies are to be added, which agents or therapies should be considered and in what order?

6.    All pathway recommendations include assurance that the patient is consistent with ongoing healthy lifestyle recommendations.

7.    Fasting LDL-C levels should be assessed regularly after the initiation of lipid-lowering medications, and every three to 12 months thereafter as appropriate.

8.    In cases of suspected statin intolerance, the provider should include temporary discontinuation of statin therapy, lower dosing, re-challenge preferably with 2–3 different statins that utilize different metabolic pathways, and intermittent (1–3 Xs weekly) dosing of long half- life statins.

9.    In selected high-risk patients (those with existing ASCVD or those with an LDL-C > 190 mg/dL), use of non- statin therapies may be considered if maximally tolerated statin therapy has not achieved > 50 percent reduction in LDL-C from baseline.

10.  Guidance on other factors are also provided including the absolute LDL-C level achieved, the extent of available scientific evidence for safety and tolerability, potential for drug-drug interactions, efficacy of additional LDL-C lowering in ASCVD event reduction, cost, convenience and medication storage, pill burden, route of administration, potential to jeopardize adherence to evidence based therapies, and, importantly, patient preferences.

The panel emphasized that LDL-C levels are not firm triggers for adding medication, however, there are factors that may be considered within the broader context of an individual’s clinical situation. Specific recommendations for add-on mediations include:

1.  A referral to a lipid specialist or registered dietitian may be considered for higher-risk patients with statin intolerance, and is strongly encouraged for patients with familial hypercholesterolemia (FH).

2.  Ezetimibe (Zetia) is the first non-statin medication that should be considered for most patients.

3.  Bile acid sequestrants (BAS) may be considered as second-line therapy who are not able to tolerate ezetimibe, but they should be avoided in patients with triglycerides > 300 mg/dL.

4.  PCSK9 inhibitors may be considered if LDL goals are not achieved on maximally tolerated statin and ezetimibe therapy in higher-risk patients with ASCVD or FH. These agents are not recommended in primary prevention patients who do not have FH.

5.  In patients with homozygous hypercholesterolemia (HoFH), referral to a lipid specialist is strongly recommended, for potential considerations for use of lomitapide, mipomerson, and LDL apheresis as necessary.