The standard theory of heart disease states that one of its major causes is the buildup of 'bad' LDL (low-density lipoprotein) cholesterol in the arteries. Eating less trans fats from meat can reduce levels, and so can drugs like statins, one of the biggest money-spinning pharmaceuticals on the market.
It follows that if cholesterol levels can be brought further down, the rate of heart deaths will also drop dramatically—but they don't. And a trial of a new type of cholesterol-lowering agent, called PCSK9 inhibitors, has proved it (although no one has noticed). In fact, far from noticing, the world's media and some doctors and researchers are predicting this newcomer is a herald of the 'post-statin era.'
PCSK9 drugs are reducing cholesterol to levels never before achieved by statins and taking medicine into clinically uncharted waters. They are halving levels of LDL cholesterol, and experts predict we will soon be seeing a corresponding drop in heart attacks and cardiovascular disease, the world's number-one killer.
Yet, the first major trial of a PCSK9 inhibitor—the FOURIER trial—has revealed that despite LDL levels dropping so dramatically, similar numbers of patients are dying with the drug as with a placebo, or sugar pill, that didn't change cholesterol levels.
Ignoring the fact that it's not saving lives, industry watchers see only two obstacles that could slow the drug's progress. First, unlike statins, which are easy-to-swallow tablets, the PCSK9 inhibitors have to be injected once or twice a month. The other is the cost of the treatment: in the United States, a one-year supply of the drug cost over $14,000 in 2015. While the price is comparatively lower in Europe, it is still equivalent to $6,800 in the UK and $8,200 in Austria.
The first PCSK9 inhibitor to gain approval is Repatha (evolocumab), made by pharmaceutical giant Amgen, which has been granted a license in more than 40 countries. Although the European Union granted its approval in 2015 for all 27 member states, the UK's NICE (National Institute for Health and Care Excellence), the gatekeeper that determines which drugs are allowed on the National Health Service (NHS), was dragging its feet.
It was one of the first to notice that there weren't any good clinical trials showing that the drug was actually saving lives.
But after some intense lobbying— mainly from patient groups who happen to get funding from Amgen and other drug companies, and who have Amgen executives on their action committees—NICE relented last year.
It's been known for several years that evolocumab could reduce LDL cholesterol levels by as much as 60 percent, and the new study—which sparked the media frenzy—confirmed that the drug is indeed reducing LDL levels by that amount, and also that it reduces the risk of heart attack, stroke, and the need for revascularization (angioplasty or bypass surgery to clear 'blocked' arteries) by around 15 percent.1
Drug vs placebo
The study recruited 27,564 people with heart disease who also had LDL levels of 70 mg per deciliter (mg/dL, the equivalent of 1.8 mmol per liter) or higher. All were already taking statins, and some were taking other heart drugs as well, such as a beta-blocker. Half were given evolocumab, and the rest got a placebo drug. In the two years the trial ran, the average LDL cholesterol level fell dramatically to just 30 mg/dL (0.78 mmol), while 1,344 people given Repatha died or suffered a heart attack or stroke, or needed revascularization, compared with 1,563 people given the placebo.
But digging deeper, the figures show that the actual number of deaths was similar in both groups: 251 with the drug and 240 with the placebo. The total number of deaths from any cause was 444 in the Repatha group and just 426 in the placebo group. A skeptic might argue that the sugar pill was more of a lifesaver than the PCSK9 inhibitor.
Yet, this didn't stop one of the researchers, Professor Peter Sever of Imperial College London, from enthusing: "The end result was cholesterol levels came down and down and down, and we've seen cholesterol levels lower than we have ever seen before in the practice of medicine."
But how can PCSK9 inhibitors reduce 'bad' LDL cholesterol to unprecedented levels and yet not save lives? The answer is simple, says cholesterol skeptic Dr Malcolm Kendrick: LDL cholesterol has nothing to do with heart disease. Instead, he suspects that air pollution—from cars, cigarettes and factories—may have more to do with the problem (see box: "Something in the air," page 22).
Dr Michel de Lorgeril, a cardiologist with the French government's National Center for Scientific Research (CNRS), has denounced the FOURIER trial as "junk science." Aside from the fact that no one seems to have noticed that more of the participants died while taking the PCSK9 inhibitor than the placebo, he is concerned that the study was designed to run for four years, but was stopped after just two.
Last November, Pfizer suddenly stopped the two SPIRE trials of its own PCSK9 inhibitor, bococizumab, even though it had recruited more than 27,000 participants. It had already completed six clinical trials into the drug, but noticed that the ability of bococizumab to lower LDL cholesterol was diminishing each time, while patients' reactions to the injections were getting worse. In fact, nearly half the 4,300 participants in the earlier studies developed antibodies that worked against the effectiveness of the drug, the company revealed in the final study it published this year.2 Nevertheless, Sanofi says its own PCSK9 inhibitor, Praluent (alirocumab), has so far been well tolerated. The drug has been approved in the US and UK.3
And buoyed by the response to the new study, Amgen is already hinting that its use could be expanded. FOURIER's lead researcher Marc Sabatine, of Brigham and Women's Hospital in Boston, says it could be time to look at other people who don't have heart disease but are producing too many PCSK9 proteins. Diabetics could also be a group, he says, and heart patients who are already taking statins but wish to get their LDL levels even lower could be another.
Amgen executives are making similar suggestions to the UK's NHS. Although NICE reversed its ban, it has allowed Repatha to be used only for people with familial hypercholesterolemia (FH), who are genetically predisposed to produce excess cholesterol. But Amgen's executive medical director Tony Patrikios says the NHS should also be looking at patients who don't respond to statins. "For them, access to new treatment options is critically important to help avoid a heart attack or stroke," he said.
So far, only the media—and the FOURIER researchers—seem to be getting excited about Repatha. Immediately after the results were announced, Amgen's share price dropped dramatically on Wall Street, while Amgen executives have revealed that health insurers in the US are refusing to fund the drug. Nearly 80 percent of claims to use the drug have been rejected by the insurance industry, and even after appeals, 52 percent were still refused.
No one quite knows exactly why Amgen ended the FOURIER study prematurely. Dr de Lorgeril has asked for all the supporting data, but it's unlikely he'll ever see them. Without that, a vital question is left hanging: did Amgen researchers stop their trial early because they were starting to see diminishing of returns similar to what killed off Pfizer's PCSK9 inhibitor?
Perhaps the birth of the post-statin era is still a little way off.
Something in the air
The PCSK9 drug trials are inadvertently challenging the cholesterol-heart disease theory. The drugs are bringing down 'bad' LDL cholesterol to unprecedented levels, and yet similar numbers of people are dying from heart attack and stroke whether taking the drug or a placebo (see main story).
Cholesterol skeptic Dr Malcolm Kendrick believes heart disease has more to do with lead from air pollution, especially from cigarettes, car exhaust and factories, which reduces nitric oxide production in the body. Nitric oxide is a molecule that regulates blood pressure and reduces inflammation.
The number of heart disease cases has been falling steadily in the developed world since the 1960s, which Kendrick believes is due to fewer people smoking, the introduction of unleaded gasoline and greater awareness of air pollution. But more recently, there's been an increase in developing countries like China and India, which, as they become more industrialized, are seeing car ownership rise.
Numerous studies support this theory. In the largest-ever study in the developing world, researchers from the Chinese Center for Disease Control and Prevention analyzed levels of air pollution in 272 typical Chinese cities.
Their average levels of air pollution were five times higher than the World Health Organization's safety levels, which means heart disease is 1.35 times more likely, the risk of hypertension nearly doubles and coronary heart disease risk increases 1.5 times.1
A similar study in China's city of Guangzhou (Canton) discovered that the risk of stroke doubled for every incremental rise in air pollution,2 while Kendrick's theory on the impact of oxidative stress was supported by yet another study that saw more ischemic heart failure in lab rats exposed to air pollution.3
It's not just restricted to developing countries either. People living near busy roads are also more likely to suffer from heart disease. One study of a community of nearly 5,000 African-Americans found that the risk of heart disorders rose the nearer they lived to a major road.4
What's in a name?
PCSK9 inhibitors are so-named because they block the protein—proprotein convertase subtilisin/kexin 9, or PCSK9—that stops certain liver cells from preventing the degradation of LDL (low-density lipoprotein) cholesterol, the supposedly 'bad' cholesterol that clogs up arteries.
As such, it's not a drug for everyone with high cholesterol, but only those who are genetically inclined to produce excess amounts of the protein. In particular, doctors have been told to prescribe the drug only to people with familial hypercholesterolemia (FH), a genetic problem that results in high levels of cholesterol, or to those who can't tolerate statins or for whom statins aren't working.
PCSK9 inhibitors are part of a larger drug family of monoclonal antibodies. These drugs are given as injections once or twice a month.