Solutions and questions came with the approval of alirocumab and evolocumab, the first two agents in a new class of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors, by the U.S. Food and Drug Administration last summer. Approved as adjunctive treatment for persistently elevated levels of LDL-C despite diet and maximally-tolerated statin therapy, these drugs are an important solution for selected patients, including adults with familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease with residual risk.

Key among the questions is whether the substantial reduction in LDL-C produced by these drugs will also reduce cardiovascular events and save lives and what is the long-term safety profile, along with the appropriate treatment algorithm and the impact of their cost.

“We are eagerly looking forward to the results of the larger outcomes trials to have a better understanding of the risk-benefit profile of the PCSK9 inhibitors,” says Christie Ballantyne, MD, FACC, chair and moderator of ACC’s LDL: Address the Risk Think Tank, which took place this past September at ACC’s Heart House in Washington, DC. The event-driven FOURIER trial with evolocumab is anticipated to be completed in 2017 and the ODYSSEY study with alirocumab in 2018.

The approval studies demonstrated good tolerability and efficacy, with reductions in LDL-C ranging from 47-56 percent with evolocumab and from 39-62 percent with alirocumab, compared with placebo, on top of maximally-tolerated statin therapy and diet.

“Statins remain the mainstay of treatment,” says Ballantyne, and have the bulk of the evidence for lowering LDL-C and hard outcomes. The emphasis continues to be matching the intensity of statin treatment to the patient’s level of risk, as first recommended by the 2013 ACC/American Heart Association guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease (ASCVD) risk, which identified four statin benefit groups.

The PCSK9 inhibitors provide a more potent drug for combination therapy with a statin, providing a greater reduction in LDL-C than the modest (~20 percent) reduction achieved with ezetimibe added to the moderate-intensity simvastatin in the IMPROVE-IT trial in high-risk patients who had an acute coronary syndromes. This was the first trial to show a benefit with the addition of a non-statin drug and provided further evidence for the LDL hypothesis of clinical benefit with lower levels of LDL-C.

For high-risk patients with clinical atherosclerotic disease and familial hypercholesterolemia, including those with true statin intolerance, “these drugs are a breakthrough that provide the first new treatment for elevated LDL-C in decades,” says Kim Birtcher, MS, PharmD, AACC, chair of the ACC’s LDL: Address the Risk Oversight Workgroup. In the absence of the hard data needed from the randomized, controlled trials with these drugs, there are preliminary data from the approval study with evolocumab suggesting a reduction in cardiovascular events and safety, although the follow-up was only 18 months.

In terms of long-term safety, experts will be looking for signals of possible downsides of lowering LDL-C to much lower levels than previously achieved. There are concerns that if LDL-C is too low there could be negative neurocognitive effects and an increased risk of diabetes and hemorrhagic stroke.

The College has published an Expert Consensus Decision Pathway on the role of non-statin therapies for LDL-C lowering in the management of ASCVD risk to complement the guidelines and bridge the gaps in clinical guidance. The document provides treatment algorithms and details the patient groups for which it is reasonable to consider a PSCK9 inhibitor and other non-statin therapies.

Before adding other treatment approaches to a statin, there should be a thorough assessment of adherence and intolerance to statin and reinforcement of all healthy lifestyle habits. In most cases, ezetimibe should be the first choice for an additional drug, and exhaustive efforts made to optimize and maximize statin therapy before considering adding a PCSK9 inhibitor. ACC’s Statin Intolerance App, which launched in 2015, is a useful tool for physicians and patients.

The nearly $15,000 annual price tag for these drugs is an issue, “particularly because of the lack of data showing a clinical gain,” says Joseph Alpert, MD, who co-chaired a scientific session yesterday that discussed the economic implications of PCSK9 inhibitors. However, he notes their cost is “not out of control” for an engineered molecule and in line with those used in hematology and oncology. The willingness of patients to contribute to the cost of these drugs is another question.

Today’s Innovation Stage presentation “Praluent^® (alirocumab) Injection: Long-term Efficacy and Safety with Two Different Dosing Regimens,” given by Paul Davis Thompson, MD, FACC, chief of the Division of Cardiology, Hartford Hospital, will review the mechanism of action, efficacy and safety data of two dosing regimens. The presentation will take place from 9:45 to 10:15 a.m. and is sponsored by Sanofi-Regeneron.

Later today, Seth J. Baum, MD, FACC, of North Ridge Heart Associates, will be giving a product overview of Repatha^® (evolocumab) in the Industry-Expert Theater 2. The presentation will take place from 12:45 to 1:45 p.m. and is sponsored by Amgen.

Thompson will also be giving a separate presentation sponsored by Amgen later today in the Innovation Stage from 3:45 to 4:15 p.m. on “A Focused Look at Unmet Need in Hyperlipidemia.”

Keywords: ACC Publications, ACC Annual Scientific Session, Acute Coronary Syndrome, Algorithms, American Heart Association, Antibodies, Monoclonal, Cholesterol, Diabetes Mellitus, Diet, Follow-Up Studies, Life Style, Stroke, United States Food and Drug Administration

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