New cholesterol-lowering drugs coming

Watch for the sleight-of-hand

• DRUG BUST by Alan Cassels

Portrait of columnist Alan Cassels
• If your aim in life is pursuing truth, one of the things you might want to study is why deception is so common in life.

– American magician Eugene Burger

Magicians are experts at directing our attention – basically manipulating and managing our perceptions. Maybe people like magic so much because we like being deceived and fooled. Houdini made an elephant disappear. An elephant! And David Copperfield once made the Statue of Liberty disappear. Incredible.

While I’ve spent a lot of time thinking of the art of misdirection and how it works in selling diseases and the drugs to treat them, it is still a most mysterious and wonderful thing. It seems even when we know we are being deceived, we don’t seem to mind. It’s almost as if we beg to be deceived over and over again.

Let’s wind the clock back a few years to the most successful example of pharmaceutical magic the world has ever seen. The drug atorvastatin (Lipitor) was launched in 1998 and over the next 13 years, before its patent expired, it earned its maker, Pfizer, upwards of $141 billion. It was the biggest commercially successful drug in the history of the world and made a lot of people very wealthy even if it did almost nothing of value to the vast majority of people who swallowed it.

Let me qualify that: if you wanted to lower your LDL (the bad) cholesterol, Lipitor was very good at that. Superb. Part of the reason for its astounding commercial success – other than Pfizer’s weapons-grade marketing power – was that it was able to lower LDL better than other rival statins on the market and Pfizer’s salespeople enticed doctors with graphs filled with curves showing how effective Lipitor was at lowering LDL compared to its rivals. Lipitor also had another marketing advantage; it had a reputation for being more potent. In the late 1990s, the statin makers were funding campaigns to get people to “know your numbers” and were responsible for a new health obsession that made people check, alter and recheck their cholesterol numbers.

I remember watching Lipitor take off in the late 1990s, astonished that the public’s love affair with the drug was completely disconnected from reality. The most amazing thing about Lipitor when it arrived to market was that there were no data showing any effect of the drug on reducing rates of heart attacks and strokes, unlike rivals such as Pravachol and Zocor. In fact, it wasn’t until mid-2004 – after Lipitor had been on the market about seven years and bagged $5.5 billion a year in sales – that the company was able to convince the FDA that clinical trials could show some tiny benefits on cardiovascular disease. This drug became an immense blockbuster well before there was any evidence – zero evidence – it could do anything except lower LDL cholesterol.

This is classic misdirection at work. Most drugs are prescribed to do something that has a positive effect on your health such as reducing your risk of cardiovascular disease and an early death. That’s what we expect. But if it only alters a blood reading? Going to great efforts to alter your LDL might be a waste of time because at the end of the day numbers are just numbers. That numeric fixation is like the sleight-of-hand used by magicians: get the audience to look in one place and they won’t realize the elephant is hiding somewhere else. In characterizing cholesterol as a killer and LDL numbers as the answer, people were manipulated into thinking that focusing on lowering numbers was good for their health.

Over the past 10 years, more recent research has shown that, given one’s age, cholesterol levels and medical history, the majority of people who take statins are in the “low risk of a heart attack” category. Which means their chance of avoiding a heart attack by taking a statin is miniscule. For example, if your risk of a cardiovascular event is 10% over the next five years, the best a statin might lower that by is 1-2% so your risk drops to 8-9%. Another way to say this is that 98-99% of the “low risk of heart attack” people who swallow a daily statin are unlikely to have any benefit related to heart health. However, they will likely have lower LDL cholesterol. Those at ‘higher risk’ – like people who have already survived one heart attack – might see a higher benefit, but even then the absolute benefits seem tiny. What’s clear is the numbers game with statins has resulted in millions of people probably taking them needlessly.

And, of course, they’re not without a range of adverse effects, such as liver damage, muscle weakness, cognitive difficulties, diabetes and other risks. For many people, that’s too high a price to pay for tinkering with some arbitrary numbers. One of the most potent statins available, cerivastatin, only lasted a few years on the market because of its tendency to cause liver failure. But boy, did it ever lower LDL!

Right now, there are two LDL busters that will surely make statins seem so “last millennium.” Amgen’s Repatha (evolocumab) and Praluent (alirocumab) made by Sanofi are known as PCSK9s (proprotein convertase subtilisin/kexin type 9). These drugs are being discussed this summer at an FDA expert committee and have been recommended for approval. A decision is likely to be made this month. Positioned to replace statins, industry analysts suggest these drugs will be priced at sticker-shock levels of $5,000-10,000 per patient per year.

Even though many doctors will wonder how the new drugs perform in relation to the statins, I’m worried they’ll still just focus on LDL. Repatha and Praluent, which are injectables, perform well in lowering LDL cholesterol so the question is: who needs them? The initial target market will likely be people with a relatively rare disease called homozygous familial hypercholesterolemia (HoFH), a genetic disorder that may lead to heart attacks in childhood, but you can bet the companies won’t stop there. The market will undoubtedly expand to those who don’t tolerate statins, those who have trouble lowering their LDL or others who want to try it “just in case.” Analysts are saying these two drugs could be worth as much as $2.5 billion a year, launching the two new drugs into the “blockbuster” category.

While all this sounds very exciting, let me pull back the curtain with two impolite questions: 1) Is it true that, like Lipitor, these drugs are coming to the market without any long-term health outcomes data (i.e. proof they prevent heart attacks or strokes) and 2) Could the drugs have nasty adverse effects (i.e. could they accidentally kill or injure people)?

The respective answers are yes and maybe. There are no long-term health outcomes data and no extensive adverse event data. Not yet. But don’t look there; look here: the drugs are ruthless LDL busters so doctors and patients worried about their LDL need to give them a try.

Seems like even the big boys are in love with the magic. The prestigious Harvard Medical School, in an article entitled PCSK9 inhibitors: a major advance in cholesterol-lowering drug therapy, waxed poetic about how the PCSK9 inhibitors are superb cholesterol-lowering agents which can lower LDL levels, compared to placebo by about 60%.

Call me a naysayer but do we really want to replay this massive deception again? Isn’t it somewhat misguided to be rushing towards new drugs that cost 10 grand a year, without a clue as to their long-term effectiveness and safety because they alter a lab value? Maybe we should give doctors the benefit of the doubt and trust they have learned the lesson of Lipitor: that it’s both silly and premature to be spending billions on drugs unless they can show anything more than impressive LDL numbers.

Or maybe, like most of us, they like to be fooled and bamboozled. After all, magic is…well, just magic.

Alan Cassels is a drug policy researcher at the University of Victoria. He writes about medical screening and drugs, consults with unions on drug benefits plans and is helping research tools to make deprescribing easier for physicians. You can read more of his writings at www.alancassels.com or follow him on twitter @akecassels

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