Resolving the lipid dilemma

If statins are not tolerated, can non-statins fill in the gap?

In 2013, the American College of Cardiology and American Heart Association (ACC/AHA) published the updated “Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults” together with a simplified guideline on the assessment of cardiovascular risk in asymptomatic individuals.

Reviewing results from randomized clinical trials (RCTs), the 2013 ACC/AHA cholesterol guideline panel put weight on evidence indicating efficacy and safety of low-density lipoprotein cholesterol (LDL-C) lowering for risk reduction which came mainly from RCTs of statin drugs. From these findings, major statin benefit groups were identified wherein risk from atherosclerotic cardiovascular disease (ASCVD) could be reduced, and the statin benefit outweighs the risk of adverse events from the drug.

Groups benefiting from statins

As a review, these four groups are:

1. Adult patients =21 years of age with clinical ASCVD;

2. Adults =21 years of age with LDL-C =190 mg/dL (not due to secondary modifiable causes);

3. Adults aged 40 to 75 years without ASCVD, but with diabetes and with LDL-C 70 to 189 mg/dL; and,

4. Adults ages 40 to 75 years without ASCVD or diabetes, with LDL-C 70 to 189 mg/dL, and an estimated 10-year risk for ASCVD of =7.5 percent.

The 2013 ACC/AHA guidelines were subsequently followed by the 2014 Joint British Societies Consensus Recommendations for the Prevention of Cardiovascular Disease (JBS3), the 2014 Veterans’ Administration/Department of Defense Guidelines on Management of Dyslipidemia, and the recent U.S. Preventive Services Task Force draft recommendations, all of which have given similar treatment recommendations.

A very important feature in the 2013 ACC/AHA guidelines was the concept of “net ASCVD risk-reduction benefit,” which aimed to determine the benefit of treatment minus the risk of potential serious adverse events with a given drug therapy.

The panel concluded that statins clearly have a positive net benefit, whereas other drug therapies available in 2013 only showed either marginal net ASCVD risk-reduction benefit or showed no additional benefit beyond what statins could offer.

The RCTs included in the review looked at fixed-dose statin therapy versus placebo, or higher-intensity versus lower-intensity statin therapy. The expert panel opined that patients treated with statin versus placebo, or with higher- versus lower-intensity statin therapy, had significantly greater ASCVD risk reduction with minimal serious adverse event rates, which were not significantly different from the adverse event rates in placebo comparator groups.

The 2013 ACC/AHA cholesterol guideline panel therefore recommended using either high- or moderate-intensity statin therapy for patients in the four statin benefit groups at risk for ASCVD in the settings of primary and secondary prevention, with dose adjustments as necessitated by factors such as adverse effects, advanced age, drug–drug interactions, and comorbidities.

The panel determined recommended an initial fasting lipid panel (total cholesterol [TC], triglycerides, high-density lipoprotein cholesterol [HDL-C], and calculated LDL-C), followed by a second fasting lipid panel four to 12 weeks after initiation of statin therapy, to determine a patient’s adherence and response to therapy. Subsequent assessments are to be done every three to 12 months.

Non-statin lipid-lowering drugs

In 2013 when the updated guidelines were released, there was no sufficient data yet supporting the routine use of FDA-approved non-statin drugs combined with statin therapy for LDL-C reduction in order to reduce ASCVD events, or to be given in statin-intolerant subjects.

However, the panel stated then: Clinicians treating high-risk patients who have a less-than-anticipated response to statins, who are unable to tolerate a less-than-recommended intensity of a statin, or who are completely statin intolerant, may consider the addition of a non-statin cholesterol-lowering therapy. High-risk individuals include those with ASCVD, those with LDL-C =190 mg/dL, and those with diabetes 40 to 75 years of age.

The broad recommendation on the use of non-statin drugs allowed for the discretion of clinicians. However, the 2013 ACC/AHA guideline panel recognized several ongoing trials then evaluating the addition of non-statin therapy to statins, such as the HPS2-THRIVE (Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events) and IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) trials, and other novel non-statin agents in development (e.g., proprotein convertase subtilisin/kexin 9 [PCSK9] inhibitors).

The HPS2-THRIVE came out in 2014 showing no benefit and possible significant harms from a long-acting niacin/laropiprant preparation in addition to moderate-intensity statin (simvastatin) compared with moderate-intensity statin alone in patients with clinical ASCVD, although additional lowering of LDL-C has been shown with niacin.

The IMPROVE-IT trial, which came out in 2015, enrolling patients with recent acute coronary syndromes (ACSs), demonstrated further reductions in LDL-C with the addition of ezetimibe to a moderate-intensity statin (simvastatin) compared with moderate-intensity statin monotherapy. There was a statistically significant, though clinically modest, reduction in cardiovascular events over seven years of follow-up, with no safety red flags in the ezetimibe group.

Just recently, the US FDA approved 2 monoclonal antibodies to PCSK9, alirocumab and evolocumab. They work by inhibiting binding of PCSK9 to the LDL receptor, thus increasing LDL receptor density. Their approved indication is the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical ASCVD who require additional lowering of LDL-C despite maximum dose of statin that could be tolerated. Evolocumab was also approved in combination with other LDL-lowering therapies like statins, ezetimibe, LDL apheresis in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

With these new agents, a dramatic reduction in LDL-C levels over and above statin therapy, has been shown with favorable short-term outcomes data up to 18 months. Long-term cardiovascular outcomes trials are ongoing for both alirocumab and evolocumab, as well as for bococizumab, and the medical community is eagerly looking forward to the results of these trials.

Expert consensus decision pathway

In the July 5, 2016 issue of the Journal of the American College of Cardiology, the ACC publised an “Expert Consensus Decision Pathway” document on the role of nonstatin therapies for low-density lipoprotein (LDL) cholesterol lowering in the management of cardiovascular disease risk.

Chaired by Donald M. Lloyd-Jones, MD, Northwestern University Clinical and Translational Sciences Institute, in Chicago, Illinois, this ‘decision pathway’ aims to advise physicians on the use of several nonstatin medications that have recently been the subject of new clinical trials so they could translate this new data (HPS THRIVE, IMPROVE-IT, PCSK9 monoclonal antibodies) into clinical practice.

The “decision pathway” includes seven different algorithms for patients with cardiovascular disease or comorbidities noting that very high-risk patients more likely may consider new drugs, though they are more expensive.

In the JACC paper, the authors explain that the algorithms endorse the four evidence-based statin benefit groups identified in the 2013 ACC/AHA cholesterol guidelines. The assumption of this algorithm is that the patient is currently on a statin, recognizing it is still the most effective initial therapy.

“Recommendations attempt to provide practical guidance for clinicians and patients regarding the use of nonstatin therapies to further reduce atherosclerotic cardiovascular disease risk in situations not covered by the guidelines,” the authors stated.

Two different algorithms for familial hypercholesterolemia (FH) are recommended assigning a lower threshold for use of PCSK9 drugs. Recommendations for diabetics and other high-risk groups who do not have cardiovascular disease are also included.

“In all these groups who are at high risk, we recommend that if LDL has not been reduced by 50 percent with lifestyle and statins then other drugs can be considered,” explained Dr. Lloyd-Jones.

The expert consensus considers ezetimibe appropriate for high-risk primary prevention, but does not think there is enough data on efficacy or safety of PCSK9 to recommend its use in primary prevention, according to Dr. Lloyd-Jones.

The apparent overall consensus is that PCSK9 inhibitors should be reserved for the highest-risk patients, such as those with ACS in whom statins could not be given due to tolerability issues. For FH, it is believed that these patients should be given immediately PCSK9 inhibitors; if this is not feasible, they should try ezetimibe first.

“If they were regular secondary prevention patients without FH, then ezetimibe should be considered first,” said Dr. Lloyd-Jones.

Summary of consensus

Salient points of the Consensus Decision Pathway:

• The 2013 ACC/AHA cholesterol guideline identified four major statin benefit groups for atherosclerotic cardiovascular disease (ASCVD) risk-reduction: (1) patients age 21 years or older with clinical ASCVD; (2) adults age 21 years or older with LDL cholesterol level of at least 190 mg/dL (not due to secondary modifiable causes); (3) adults aged 40 to 75 years without ASCVD but with diabetes and an LDL cholesterol level of 70 to 189 mg/dL; and (4) adults aged 40 to 75 years without ASCVD or diabetes who have an LDL cholesterol level of 70 to 189 mg/dL and an estimated 10-year risk for ASCVD of 7.5 percent or greater, as determined by the Pooled Cohort Equations.

• Recommendations in the 2013 guideline included using high- or moderate-intensity statin therapy for primary and secondary prevention scenarios, with dose adjustments as necessary for adverse effects, advanced age, drug-drug interactions, or comorbidities. The current Expert Consensus Decision Pathways rely on the evidence base established by the 2013 guideline and incorporate newer clinical trial data on niacin, ezetimibe, and the recently approved PCSK9 inhibitors (alirocumab and evolocumab).

• The 2013 guideline provided a framework for addition of non-statin therapies that the current Expert Consensus Panel has used to provide more detailed recommendations for specific patient scenarios. The Expert Consensus Panel addressed three questions:

1. In what patient populations should nonstatin therapies be considered?

2. In what situations should nonstatin therapies be considered (ie, when is the amount of LDL cholesterol lowering [percentage LDL cholesterol reduction or LDL cholesterol range achieved on therapy] less than anticipated, less than desired, or inadequate?), and which treatment options should be considered in patients who are truly statin intolerant?

3. If nonstatin therapies are to be added, which agents or therapies should be considered and in what order? All pathways for nonstatin therapy recommendations include assuring that the patient is following a healthy lifestyle.

• Consistent with the recommendations of the 2013 guideline, fasting LDL cholesterol levels should be regularly assessed after initiation of lipid-lowering treatment and every 3 to 12 months thereafter as indicated.

• The approach to suspected statin intolerance should include temporary discontinuation of statin therapy, lower dosing, rechallenge (preferably with two to three statins of differing metabolic pathways), and intermittent (one to three times weekly) dosing of long half-life statins.

• In selected high-risk patients, such as those with existing ASCVD or LDL cholesterol level of 190 mg/dL or greater, use of nonstatins may be considered if maximally tolerated statin therapy has not achieved greater than 50% reduction in LDL cholesterol from baseline.

• The pathways also provide guidance on other factors that should be considered regarding the addition of nonstatin therapies, including the absolute LDL cholesterol level achieved, the extent of available scientific evidence for safety and tolerability, potential for drug-drug interactions, efficacy of additional LDL cholesterol 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 Expert Consensus Panel emphasizes that LDL cholesterol levels are not firm triggers for adding medication, but they are factors that may be considered within the broader context of an individual patient’s clinical situation.

• Referral to a lipid specialist and registered dietitian may be considered for higher-risk patients with statin intolerance and is strongly encouraged for patients with FH.

• Ezetimibe is the first nonstatin medication that should be considered in most of the patient scenarios, given its safety and tolerability, as well as demonstrated, though modest, efficacy when added to moderate-dose statin in one trial of patients with acute coronary syndrome.

• Bile acid sequestrants (BAS) may be considered as second-line therapy for patients in whom ezetimibe is not tolerated, but they should be avoided in patients with triglycerides greater than 300 mg/dL.

• Alirocumab and evolocumab may be considered if the goals of therapy have not been achieved on maximally tolerated statin and ezetimibe in higher-risk patients with clinical ASCVD or FH. Given the lack of long-term safety and efficacy data on these agents, they are not recommended for use in primary prevention patients in the absence of FH.

• For patients with homozygous hypercholesterolemia, referral to a lipid specialist is strongly recommended with statins, and nonstatins including ezetimibe, BAS, with consideration for use of lomitapide, mipomersen, and LDL apheresis as necessary. LDL apheresis is also approved for heterozygous FH. With J Am Coll Cardiol. (2016) and Medscape reports

Vital Signs July 1-31 2016