If you watch or read the news lately, you might think that an amazing new miracle drug to combat high cholesterol is about to change the world.
Last week, the New England Journal of Medicine published a big new study about a cholesterol drug called Repatha. The hype has been pretty hard to miss. Late-night news is trumpeting a “breakthrough,” anecdotes about patient miracles abound, and there have been wall-to-wall commercials urging people to ask their doctor about the treatment.
When the Food and Drug Administration first approved Repatha in 2015, it indeed seemed promising. Since the 1980s, people with high cholesterol have had one main treatment option: statins, such as Lipitor. Repatha, and other similar cholesterol-lowering medicines known as PCSK9 inhibitors, seemed to dramatically reduce cholesterol levels — even more so than statins.
But a huge question remained: Could these drugs actually cut the incidence of strokes or heart attacks? That’s what the new NEJM study sought to find.
After reading the study, and talking about it with doctors and researchers, I’m skeptical about the hype. Repatha isn’t as promising as many of the news reports suggested. In fact, the drug is raising questions about whether there’s a threshold for cholesterol lowering, beyond which health benefits simply may not manifest.
Drugs like Repatha lower cholesterol by dramatic amounts — but that hasn’t yet translated into cutting people’s risk of death
So far, there are two PCSK9 inhibitors on the market: Amgen's evolocumab (a.k.a. Repatha) and alirocumab (brand name Praluent), which is produced by Sanofi and Regeneron Pharmaceuticals. These drugs are self-injected every two weeks, and work by blocking the PCSK9 protein, which is believed to slow the body's ability to rid the blood of LDL (or "bad") cholesterol, a major risk factor for cardiovascular disease.
The early clinical studies on PCSK9 inhibitors showed they lowered cholesterol by truly dramatic amounts. In the big 2015 clinical trial on Repatha, also published in NEJM, the drug reduced patients' LDL cholesterol levels by 61 percent, from a median of 120 milligrams per deciliter to 48 milligrams per deciliter. Another big study on Praluent uncovered a similar result. Even patients already on statins saw their blood cholesterol levels drop further when they injected these drugs.
These studies were important, but they did not delve into whether the drugs had an impact on real-world outcomes, such as death and disease, above changing lab markers like cholesterol.
That’s why there’s been so much coverage of this new Repatha study: It’s the first high-quality, real-world trial on the effects of PCSK9 on death and disease — giving doctors, researchers, and insurance companies a clearer picture of what all that cholesterol lowering does to people’s health in the longer term.
The study followed more than 27,000 patients, at more than 1,200 sites in 49 countries, for about two years. The patients were assigned either to take Repatha and statins together or to take statins along with a placebo. Repatha reduced the combined risk of heart attacks, strokes, and other cardiovascular problems by 15 percent compared with the placebo group.
But this is also important: The drug had no effect at all on mortality. So despite lowering cholesterol considerably, and reducing the risk of strokes and heart attacks, it didn’t cut people’s risk of death. These results weren’t nearly as dramatic as what industry watchers and doctors had hoped for. (Cardiologists have said anything less than a 20 percent cardiovascular risk reduction means the drugs aren’t clinically relevant, and Amgen’s stock dropped by 7 percent after the study was published.)
To understand why, let’s look at the study in more detail. The findings suggest that if a person took Repatha on top of her statins for about two years, she’d decrease her risk of a heart attack by about a percentage point, from 4.6 percent to 3.4 percent. She’d also cut her risk of stroke from about 2 percent to 1.5 percent, or half a percentage point.
In real terms, that means 80 people would have to take the drug for about two years to prevent one heart attack, and 250 would have to take it to prevent one stroke. If you think that sounds pretty good, consider this: The drug costs $14,100 a year for patients, which is about 50 times the cost of generic statins — drugs that doctors have pointed out carry about the same level of benefit as Repatha.
“This may be worth it to some people,” said Vinay Prasad, a professor of medicine at Oregon Health and Sciences University. “To others, that may be a lot of injections and a lot of hassle to prevent one stroke.”
By Prasad’s estimation, only 40 people would need to take statins to prevent one heart attack, and 83 to prevent a stroke. What’s more, he added, statins have also shown mortality benefits — and Repatha hasn’t yet been proven to reduce the risk of death. So statins seem to be a much better deal for patients.
The fact that Repatha can cut cholesterol so significantly, but not deliver dramatic benefits to health, also raises questions about the impact of cholesterol lowering beyond a certain point.
“There could be an LDL threshold below which more clinical benefit not likely attained,” said Eric Topol, a cardiologist and director of Scripps Translational Science Institute. “We don’t know.”
Topol was also skeptical about the hype. “The trial was disappointing due to the disproportionate, large reduction of LDL but only modest effect on outcomes [such as] heart attack and stroke reduction,” he said.
Still, he pointed out that perhaps the two-year follow-up in the study wasn’t long enough to uncover a mortality benefit, so more studies may eventually show that effect. Amgen has been arguing as much in its defense, but as drug developer Derek Lowe wrote on his blog, that argument is a little dubious since Amgen helped design the trial, presumably choosing a study design that would generate the most favorable data.
At more than $14,100 per year, are the drugs worth it?
The big question this raises now: Is Repatha worth it?
Again, the drug costs $14,100 per year. Until now, insurance companies and pharmacy benefit managers have been rejecting a majority of the claims for Repatha (and the other PCSK9 inhibitor, Praluent) because the drugs’ effects on cutting health risks and hospitalizations weren’t known before the latest NEJM study.
It’s not clear whether the new data will make them change their minds. At Repatha’s current price, it costs $2.4 million to prevent a single heart attack and $7.5 million to prevent a stroke, according to Prasad.
“These numbers are incredibly high,” he said. There may be cheaper ways to achieve similar benefits, he added, such as simply increasing statin doses in patients.
It is possible that more and better data might come out that shows Repatha is the miracle we’ve been waiting for. It’s also possible that with longer follow-up times, more side effects could be uncovered too. The clinical trial showed an increased risk of diabetes in Repatha users, for example. Topol pointed out at least four in 1,000 patients will develop diabetes induced by the drug. That picture could change as we learn more.
For now, the drug seems to hold the most promise for people who can’t take statins or in whom the drugs don’t always work well, such as some people with familial hypercholesterolemia. Repatha may be helpful for this small group — it just may not be the blockbuster breakthrough the industry and patients had been hoping for.