A new class of drugs, separate from statins, has generated excitement among cardiologists and prompted talk about a possible “new era” in treatment to lower so-called “bad,” or LDL, cholesterol.

Research shows the biological agents — called PCSK9 inhibitors for the protein in the liver they block that helps regulate LDL cholesterol — have a powerful ability to lower high LDL, which is linked to heart attack, stroke and other cardiovascular issues. The drugs’ efficacy seems to extend beyond what statins alone can do in some patients.

“Sometimes statins aren’t quite enough to reduce [cardiovascular] risk. So the opportunity to supplement statin therapy, which will always be the foundation for lowering cholesterol, is an exciting prospect,” says Dr. James Januzzi, a cardiologist at Massachusetts General Hospital in Boston, and professor of medicine at Harvard Medical School, who is not involved in research on the nonstatin drugs.

The Food and Drug Administration is expected to make a decision as early as this summer regarding approval of the first two PCSK9 inhibitors — evolocumab (Repatha) made by the pharmaceutical firm Amgen, and alirocumab (Praluent), developed by Sanofi and Regeneron Pharmaceuticals.

PCSK9 inhibitors are expected to supplement, though not replace, widely prescribed statins in some patients. “Statins are clearly the standard of care,” says Dr. Seth Martin, a cardiologist at Johns Hopkins University in Baltimore. Taken by roughly 25 million Americans today, clinicians have long prescribed statins as a go-to therapy to reduce the risk of heart attack and stroke in patients, by lowering cholesterol. In generic form, statins can now be purchased for as low as $4 a month.

Still, research shows some patients, who don’t see high LDL knocked down enough by statins alone, appear to benefit from also taking PCSK9 inhibitors. In particular, that includes individuals with a genetic condition called familial hypercholesterolemia, which is characterized by strikingly high cholesterol levels.

“These are people who would present with a heart attack early in life in their 30s or 40s,” Martin says. They have 200 to 300 LDL, he adds, roughly two to three times that of the average American, who has an LDL of around 100.

A recent review of 24 studies that looked at the effect of PCSK9 inhibitors on more than 10,000 patients with hypercholesterolemia found the drugs cut LDL cholesterol levels roughly in half, and reduced mortality rates, such as from heart attack.

Martin cowrote an editorial that accompanied the study published online in the Annals of Internal Medicine April 28.

About 1 in 300 to 500 patients suffers from hypercholesterolemia, he says, and other individuals don’t see cholesterol lowered enough by statins alone. In addition, some patients can’t take statins because of the muscle pain they experience — a known side effect of the drugs.

“A substantial number of patients who get prescribed statins actually can’t tolerate them because of the side effects … typically muscle cramps,” Januzzi says. “It’s surprising how frequently those side effects occur.” By comparison, studies show a lower incidence of such side effects for patients given PCSK9 inhibitors.

Martin and others cautioned, however, that the 24 studies reviewed were small to moderately-sized with a relatively short follow-up period. Experts say yearslong, large, controlled studies are needed to get a clear understanding of whether the drugs could extend patients’ lives, and any harm they might cause as well.

Some study participants have reported neurocognitive effects such as “fuzzy thinking” and difficulty remembering, Martin says, after taking PCSK9 inhibitors, which are administered by once- or twice-monthly injections versus statins, which are taken daily in pill form. Less significantly, some patients experienced mild skin reactions at the injection site.

“Statins have been shown to unmistakably be associated with the potential for neurocognitive side effects, such as memory impairment, low-grade confusion [and] nightmares,” Januzzi says.

He says it’s too early to tell how PCSK9 inhibitors will compare, in terms of potential neurocognitive effects, but adds that it’s worth exploring further.

Martin says the proportion of PCSK9 patients reporting neurocognitive adverse events is low, about 1 percent, but that it remains a point of focus. “It’s something that’s being closely monitored by the FDA right now,” he says.

Similarly, more study will be required to determine if PCSK9 inhibitors could increase a patient’s risk of developing Type 2 diabetes, something recent research has shown statins do.

“It’s a small effect, [but] it’s not trivial,” says Dr. Steve Nissen, chairman of the department of cardiovascular medicine at Cleveland Clinic in Cleveland. Still, he finds the effect statins have on diabetes risk less compelling than the drugs’ ability to lower cardiovascular risk. “It hasn’t changed how we use the drugs,” he says.

Nissen, who is involved in studies on PCSK9 inhibitors, says so far, he isn’t aware of an influence on diabetes risk, but adds that he’s keeping an open mind.

As risks continue to be studied, Januzzi points out another potential benefit of PCSK9 inhibitors: their ability to lower levels of something called Lipoprotein(a).

“Higher levels of Lp(a) have been linked to higher risk for the onset of coronary artery disease,” he says. “In fact, back in the 1980s, the tennis great Arthur Ashe had normal cholesterol levels but was found to have very high Lp(a) concentrations when he was diagnosed with coronary disease.”

Previously, no medications existed to lower Lp(a), molecules comprised of protein and fat that carry cholesterol and other substances through the blood. “The idea of lowering Lp(a) as a way to reduce heart risk has never been tested. But now with the PCSK9 inhibitors, this becomes a testable hypothesis,” he says, though he reiterates, at present, it remains just a hypothesis.

What’s more, Januzzi notes that researchers found the new drugs also bump up good cholesterol, or HDL. Patients’ HDL levels increased by about 6 percent, compared with placebo, according to the review of research published in the Annals of Internal Medicine in April.

Still — for all their touted promise — cost looms large in physicians’ considerations of how they’ll prescribe PCSK9 inhibitors, pending expected approval of the first drugs for market.

“Given how expensive these drugs are going to be, at least to start, it’s not going to be for everyone,” Januzzi says. “They’re still not going to be first-line therapies.”

Rather, the focus will be high-risk patients, cardiologists say, which could still number in the millions, such as those who have familial hypercholesterolemia, and other patients with high LDL cholesterol, not reduced enough by statins, who have already suffered heart attacks or other cardiovascular events.

The injectable drug could cost upward of $12,000 a year, according to preliminary estimates. Experts say that will likely lead insurers to take a hard look at which patients to approve — and reject — for the treatment coverage. “Physicians and patients are sometimes caught in the middle in these circumstances,” Januzzi says.

That’s true, too, for statins, which came under fire as being too widely recommended to patients following guidelines issued in November of 2013 by the American College of Cardiology and the American Heart Association, which advised further expanding their use.

Statins bear the distinction as the most prescribed class of drugs in the world.

To determine what’s best for the individual, Martin advocates patients and their physicians engage in shared decision-making, weighing cardiovascular risks against the risk of taking the drugs themselves, whether statins or PCSK9 inhibitors post-approval.

“This is not an automatic thing that you follow some algorithm and immediately prescribe something. This should happen in the context of coherent, thoughtful care,” Martin says, with a patient talking to his or her physician about their current cardiovascular risk, their current management strategy to reduce that risk and other treatment options. “This would be one potential option,” he says.

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Nonstatin Cholesterol-Lowering Drugs Show Promise originally appeared on usnews.com