- The Food and Drug Administration just approved evolocumab (brand name Repatha), the second of a new class of cholesterol-lowering drugs (PCSK9 inhibitors) to get the green light.
- These PCSK9 inhibitors are being touted as "one of the biggest developments in a long time in cardiology" and "a triumph of the modern genetic revolution."
- Critics aren't so sure. They have expressed concerns about the safety and efficacy of this new class of medicines, pointing out that the long-term safety data isn't in yet and that it's unclear whether these drugs will have an impact on heart attacks and death.
The FDA just approved new cholesterol-lowering drugs
Since the 1980s, people with high cholesterol have had one main drug choice: statins, such as Lipitor.
Statins are important because they lower the risk of heart disease, stroke, and heart attack. But there are patients who can't tolerate statins, and others with genetic disorders such as familial hypercholesterolemia who cannot lower their cholesterol enough to see a benefit on statins alone.
This is why doctors have been really excited about a new class of cholesterol-lowering medicines known as PCSK9 inhibitors. These drugs are self-injected every two weeks, and work by blocking a protein (PCSK9) that seems to slow the body's ability to rid the blood of LDL (or "bad") cholesterol.
The discovery of this targeted therapy came about after scientists learned more about how the liver flushes out bad cholesterol and noticed that people with genetic defects who lacked PCSK9 seemed to have very low cholesterol levels.
So drug companies set out to create a therapy with the same effect, and they came up with Amgen's evolocumab and another recently FDA-approved drug called alirocumab (brand name Praluent) by Regeneron Pharmaceuticals.
So far, studies on the drugs appear to be promising. In the big clinical trial on evolocumab, published in the New England Journal of Medicine, the drug reduced patients' LDL cholesterol levels by 61 percent, from a median of 120 milligrams per deciliter to 48 milligrams per deciliter. The big study on alirocumab, also published in the New England Journal of Medicine, uncovered a similar result. Even patients already using statins saw their blood cholesterol levels drop further.
On the basis of these results, experts are expecting PCSK9 inhibitors to be the biggest blockbuster heart drugs since statins emerged in the 1980s.
It's not clear these drugs actually cut the risk of heart attacks
All this fanfare should come with some major caveats, say medical experts. Harlan Krumholz, a cardiologist and professor of medicine at Yale University, noted that the studies we have so far only looked at lab test results on LDL levels. In other words, they did not test for whether the drugs had an impact on real-world endpoints, like death and disease. (In both of the New England Journal of Medicine studies, researchers did post hoc analyses on cardiovascular events and found the drugs had a positive effect — but that's not the same as designing a clinical trial with heart attacks and death as the primary outcomes under study.)
Studies looking at the drugs’ effectiveness in cutting heart attacks and deaths are expected to come out in 2017. For now, Krumholz noted that the medical community has been fooled many times by early studies that "make your blood tests look better but they don't actually make patients better."
What's more, because the studies only ran for months — and not the years many patients would use the drugs for — the longer-term impact of using these injectables on the body isn't yet clear.
"These studies compared to the general population are small, and they were done in selected patient populations that were followed for a short period of time," said Julie Clary, chief cardiology fellow at the Krannert Institute of Cardiology at Indiana University. "Only time will tell about the long-term effects, the long-term benefits, and how they’re working in the general population outside of just the clinical trials sphere."
Critics are concerned about side effects and costs
"All drugs we use have thousands of effects," Krumholz added. "When we measure the drug's on effect on blood cholesterol, that's just one endpoint. Because the drug is doing other things, too, it's hard to know what happens when you test it out in a lot of people."
Eric Topol, a cardiologist and director of Scripps Translational Science Institute, said he also had concerns about potential side effects. In the trials, fewer than 1 percent of participants experienced a cognitive impairment such as memory loss.
"We don't know why that's the case," he said. "And what happens when you put a drug out there in a real world, when they have vast exposure to many people — signals you see in clinical trials usually get worse." In other words, he expects more people might complain about these side effects when these drugs reach the market.
There's also the issue of cost. The medicines are expected to come with a price tag of $7,000 to $12,000 per patient per year, according to the Wall Street Journal's Pharmalot blog, costing the US health system as much as $23 billion a year. "These injectable drugs are already viewed by payers as potential budget busters along the lines of treatments for hepatitis C and some cancers," Ed Silverman wrote.
To mitigate some of the risk, the FDA has approved these drugs for use in targeted populations — for those with familial hypercholesterolemia or who have cardiovascular disease and need to lower their cholesterol levels further.
But even if the drugs are approved for limited use, this doesn't mean doctors won't prescribe them more freely. "The problem is," said Topol, "how do you keep it segmented for those people in the jungleoid medical world of prescribing things where doctors have the discretion of using these drugs any way they like and patients are asking for it."