When to Consider an Alternative to Statins

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Since the 1980s, statins have been the medication of choice for lowering elevated levels of LDL cholesterol and reducing the risk of heart attack. Generally the drugs are safe and effective. For some patients, however, that’s not the case: Their LDL levels remain stubbornly high or they develop intolerable side effects, such as persistent muscle pain.

Other types of cholesterol-lowering drugs have long been around; the problem, though, is that evidence of their benefits is lacking. Statins are the only class of cholesterol medication that has been shown, in multiple large-scale randomized controlled trials, to reduce the risk of heart attack and stroke. That picture may be changing, however, as effective alternatives make their way through the regulatory process.

The PCSK9 inhibitors

In the past several years, a group of experimental drugs known as PCSK9 inhibitors has shown promise in clinical trials: They drastically cut LDL cholesterol, and they work for people taking statins whose LDL remains well above desirable levels, as well as for those who can’t tolerate statins because of side effects such as muscle pain.

The U.S. Food and Drug Administration in 2015 approved the first two medications in this class: alirocumab (Praluent) and evolocumab (Repatha). However, the drugs have been approved only for a select group of high-risk patients. They include people with extremely high cholesterol levels and those with heart disease whose cholesterol levels cannot be lowered sufficiently with statins and other therapies.

The drugs work by blocking a specific protein in the liver, proprotein convertase subtilisin/ kexin type 9, or PCSK9, which then allows more LDL cholesterol to be removed from the blood. In a review of 24 clinical trials published in the Annals of Internal Medicine in 2015, researchers found that PCSK9 inhibitors substantially lowered LDL cholesterol—by an average of 47 percent in the more than 10,000 participants studied when compared to either a placebo or another LDL-lowering drug, ezetimibe (Zetia). The review also found that the drugs reduced patients’ risk of heart attack and death from heart disease over about a one- to two-year follow-up.

Some trials included in the review focused on people who had stopped taking statins because of side effects, while others involved people with familial hypercholesterolemia—a condition that causes abnormally high LDL levels that are often resistant to statin treatment.

A separate study, published in The New England Journal of Medicine in 2015, included almost 4,500 patients who had experienced statin side effects or were not getting enough benefit. Some were randomly assigned to take evolocumab along with their usual treatment (such as a statin or ezetimibe), while the rest stayed with their usual care alone.

Over one year, patients on evolocumab saw their LDL drop by 61 percent, on average, compared with the group on standard therapy alone. What’s more, their risk of heart attack and other cardiovascular complications was cut in half—from almost 2.2 percent to just under 1 percent.

Why more study is needed

There are important caveats, however. All of the PCSK9 studies have been fairly short term, and few patients have actually suffered heart attacks or other complications. With such small numbers, it can be difficult to determine how effective the drugs really are. An editorial that accompanied the Annals of Internal Medicine review called the trial results encouraging, but cautioned that the trials to date have been of small or moderate size and that long-term, ongoing pivotal trials are needed to confirm these results.

In addition, the drugs’ long-term safety has to be monitored. It appears that they do not cause muscle-related side effects. But one concern that emerged from the trials is the potential for neurocognitive effects. Some study participants have reported problems such as confusion and difficulty concentrating—although it isn’t clear that the medications are to blame. The FDA has said it is paying close attention to the issue. Long-term safety and efficacy data aren’t expected before clinical trials wrap up in 2017.

Time will tell if the PCSK9 inhibitors match statins when it comes to preventing heart attacks and strokes. Even if they prove their worth, some obstacles may remain. For one, the drugs are self-injected, which may deter some people from trying them. However, the injections are needed only every two to four weeks, which might be preferable to a daily pill. Cost may be another stumbling block: The two newly approved drugs are each priced at upwards of $14,000 a year.

Ezetimibe

Another option for people at risk is the cholesterol absorption inhibitor ezetimibe, which works by reducing the intestinal absorption of cholesterol—a distinct mechanism unrelated to that of statins or PCSK9 inhibitors.

Results of a clinical study of the drug Vytorin, which combines ezetimibe with the statin simvastatin (Zocor), showed that patients taking Vytorin had a lower risk of having a heart attack or stroke, or of dying of cardiovascular causes, compared with patients taking simvastatin alone. Over seven years, 13 percent of Vytorin users had a heart attack, versus 15 percent of those taking simvastatin. In general, the benefit seemed greatest for patients with diabetes and those older than 75. Results of the clinical trial, called IMPROVE-IT, were published last year in The New England Journal of Medicine.

Earlier studies had indicated that Vytorin reduced LDL by a greater degree than a statin alone, but the significance was not clear. Greater LDL reductions matter only if they reduce cardiovascular events. Results from IMPROVE-IT clarified the benefit—albeit a modest one—of adding ezetimibe to a statin. The findings validate the theory that lowering LDL is key—and suggest that drugs other than statins can ward off heart trouble.

Are you a candidate?

No one expects statins to be replaced as the go-to cholesterol drug. They’re proven to lower the risk of heart attack, stroke, and premature death; many people have no significant side effects; and they’re available as inexpensive generics.

But now there are options for people who do not fare well, or well enough, on a statin. This is not a small group: Studies suggest, for example, that anywhere from 5 to 20 percent of statin users have reported muscle problems—although it’s not clear that the medications are always to blame.

One 2015 study, published in the American Heart Association journal Arteriosclerosis, Thrombosis and Vascular Biology, found that about 20 percent of people with coronary heart disease showed no significant improvement in their LDL levels after starting a statin. Some even saw their LDL continue to rise. The study, an analysis of seven clinical trials, found that artery-clogging plaques tended to build up at a faster rate in people whose LDL did not respond to a statin.

If statins have not worked well for you, it’s important to talk with your doctor about the newer options.

Learn more about the possible effects of statins on memory and how you can improve your heart health through diet.