Features July 2014 Issue

Encouraging Research Shows New Cholesterol Busters Safe, Effective

For those who don't tolerate or benefit from statins, proof is building for a new class of drugs designed to reduce cholesterol.

The subject of cholesterol is dominating the headlines. Whether it’s about the drugs used to reduce high cholesterol levels or who should be treated, the topic is one that both healthcare professionals and their patients are actively discussing.

The new cholesterol guidelines released in November 2013 from the American College of Cardiology (ACC) and the American Heart Association (AHA) have moved away from achieving target cholesterol levels. Lowering the overall risk of heart disease and stroke is instead being done by identifying and treating high-risk individuals with appropriate doses of statins. The way in which high cholesterol levels are being treated remains central to the bottom line of good health. Even as statins remain the primary therapy for cholesterol reduction, a new class of experimental medicines, known as PCSK9 inhibitors, may soon offer an alternative for patients who are unable to benefit from statin drugs.

Results from large trials studying the medications, released at the ACC conference (March 2014), support previous smaller studies that showed dramatic reduction in cholesterol levels with use of the drugs. The new research shows PCSK9 may reduce LDL cholesterol levels 50 to 70 percent in patients not on statins, those on both high- and low-dose statins, and in populations of patients who can’t achieve aggressive goals due to statin intolerance or the genetic disorder heterozygous familial hypercholesterolaemia, according to Michael Rocco, MD, Medical Director of Cardiac Rehabilitation and Stress Testing and staff cardiologist at Cleveland Clinic.

“A year ago we knew that these drugs, in small trials, were very efficacious in terms of lowering LDL cholesterol,” says Dr. Rocco. “What we’ve built upon, based on data presented at this year’s ACC meeting, is that the efficacy and safety hold up over longer-term trials, and it’s consistent across a broad range of patients.”

A way to avoid side effects?
About 25 million people in the United States take statin drugs, including atorvastatin (Lipitor®), simvastatin (Zocor®) and rosuvastatin (Crestor®), to manage high cholesterol levels. In addition, up to 56 million are candidates for therapy based on the new guidelines. Yet, 10 to 20 percent of those patients may be statin intolerant due to side effects such as persistent muscle aches, weakness, gastrointestinal symptoms and liver problems.

“Statin intolerance is a bigger problem in the real world than we’re seeing in clinical trials,” explains Dr. Rocco. “To find a drug that is well tolerated and very efficacious with a good safety profile is good news for these patients.”

Proof behind PCSK9 inhibitors as an alternative to statins is shown in the Phase 3 GAUSS-2 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2) trial. The study, published in the Journal of American College of Cardiology (March 2014), focused on Amgen’s version of PCSK9 called evolucumab (also known as AMG-145). After treatment once or twice monthly, patients had reductions in LDL-cholesterol levels in the range of 53 to 56 percent. This was compared to a reduction of 15 to 18 percent among those treated with ezetimibe (Zetia®).

Currently, there are other PCSK9 drugs in development. Sanofi and Regeneron Pharmaceuticals’ alirocumab and Pfizer’s bococizumab are both being studied in phase 2 and phase 3 studies.

“While the GAUSS-2 trial showed similar reductions in LDL cholesterol compared to other studies reviewing PCSK9 drugs, all the patients in the trial were selected due to muscle symptoms and complaints (unable to tolerate two or more statins),” says Dr. Rocco. “When taking evolucumab the number of muscle complaints was quite low, and in fact, lower than in those taking ezetimibe. This is very encouraging and suggests the mechanism of muscle problems with statins may be bypassed with use of this drug.”

More positive proof
In the LAPLACE-2 (LDL-C Assessment with PCSK9 MonoclonaL Antibody Inhibition Combined with Statin Therapy) study, which also evaluated Amgen’s evolucumab, patients were treated once every two weeks or once monthly and were also treated with a variety of background therapies, including high-dose/low-dose atorvastatin and rosuvastatin and simvastatin. The trial showed a reduction in LDL cholesterol from 63 to 75 percent.

Additional results from the DESCARTES (Durable Effect of PCSK9 Antibody CompARed wiTh PlacEbo Study) trial published in the New England Journal of Medicine (March 2014) looked at 901 patients with hypercholesterolemia taking 420 mg of evolocumab once every four weeks for one year. Treatment with the PCSK9 inhibitor significantly reduced LDL-cholesterol levels 57 percent from baseline at 52 weeks in all participants.

Finalizing the equation
The fact that 12 different oral and poster presentations involving this class of drug were offered at the ACC meeting highlights the interest. As PCSK9 continues to pick up momentum in efficacy and safety, the third and important part of the equation that remains unknown is whether long-term use of these drugs will be effective in reducing cardiovascular events, according to Dr. Rocco.

“There are three long-term studies that have begun to look at the cardiovascular benefits of PCSK9 inhibitors, but it will be late 2017 or early 2018 before we know the outcome,” he says. “The reality of approval by the Food and Drug Administration (FDA) sooner than later is accepting that there may be an unmet need for those who can’t see the benefits of statins. These include individuals unable to take statins due to intolerance or inability to effectively lower cholesterol to acceptable levels on statins.

“I don’t think PCSK9 inhibitors will replace statins as first-line therapies due to the large body of evidence for benefit with statin therapy,” says Dr. Rocco. “Yet, if randomized controlled trials show incremental benefit on top of maximally tolerated statin therapy or in those unable to tolerate statins, I think they will be an important medication to have in our arsenal for those not effectively treated with current therapy.”

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