More cholesterol craziness

DRUG BUST
by Alan Cassels

Ask if Repatha can get you on the path to way lower LDL. – Advertisement for the new LDL-lowering drug Repatha.

Some days I love this crazy drug world where there is a never-ending trove of stories that continue to amaze and entertain. This summer, it’s worth introducing my readers to a very new and ultra expensive class of cholesterol-lowering drugs known as proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors. They do an amazing job of lowering LDL, known as the “bad” cholesterol.

Certainly, on that parameter alone, they are much better than the oft maligned statins, but the main question is whether governments, and individuals, will be able to afford PCSK9 inhibitors. At $8,000 or so per year, this injectible drug will cost about 50 times more than statins.

While I’ve often maligned statins myself, it’s more due to the very real questions around the alleged dangers of ‘high’ cholesterol and what kind of meagre impact we see when medicating a normal and vital substance in our blood. To summarize in one sentence the arguments I’ve made over the last decade, lowering cholesterol with statins makes astonishingly small differences to the length and quality of most people’s lives.

Even for those who are at ‘very high’ risk of a heart attack or stroke, taking daily statins for five years might, at best, reduce their risks by two to three percent. Which is to say, 97 to 98% of people swallowing a daily statin are unlikely to see any benefit from them. Besides wasting their money and unnecessarily exposing themselves to statin dangers such as muscle weakening, cognitive effects and other bad effects, people can do many more things to improve their cardiovascular health.

So along come the PCSK-9s with another aggressive war on high LDL and some pundits predicting “blockbuster” status for these drugs. Some predictions say this class of drugs could cost as much as $100 billion per year in the US, making the PCSK9 inhibitors the costliest drug therapy class in the history of humankind. As we surpass new heights on the pinnacle of pharmaceutical absurdity, I am still jaw-droppingly awed by the length to which we humans will go to medicalize and medicate our cholesterol levels. And because of the mind-boggling amounts of money at stake, you can imagine there will be lots of high-priced rhetoric in the medical press working to get you to take these drugs.

The first two approved PCSK9 inhibitors in Canada are alirocumab (Praluent™) and evolocumab (Repatha™). They are approved for “the treatment of primary hyperlipidemia and mixed dyslipidemia (high levels of “bad” cholesterol).” Basically, looking at the ads, they seem to be pitched to anyone who requires “additional lowering of LDL-cholesterol.” In other words, “all of us.”

Let me summarize six reasons why you should probably not get too excited by this new class of drugs and why we need to be skeptical of many new drug claims.

1. Big trials: If you have to enroll a ton of people into your trial, that’s a sign the drug has a very small effect. The Praluent (ODYSSEY) trial enrolled 18,000 patients and the Repatha (FOURIER) trial enrolled 27,000 to see if the drugs reduced cardiovascular risk. Another trial (SPIRE-1 and 2) testing Pfizer’s PCSK9 inhibitor, bococizumab, enrolled 32,000 patients and was stopped early because even with that many people, the drug turned out to be a dud.

2. Exaggeration of the treatment effects: Many media reports on the PCSK9 inhibitors tended to exaggerate the effectiveness of the drugs, saying they reduced the risk of heart attack and other major cardiovascular problems by “more than half,” compared with standard treatment alone. One study in the New England Journal of Medicine showed patients taking evolocumab had about a 1% risk of cardiovascular events compared with 2.2% in the control group, for a 1.2% absolute risk reduction. But since one is “50% less” than two, you can imagine how the spin doctors repeat ad nauseam the impressive sounding “50% reduction.” Basically, it’s better to say the drug reduces risk by “50%” than to say the drug may have helped one in 100 people, which, um, is not so impressive.

3. Too many safety unknowns: Like any new drug, there are things we don’t yet know. The concerns here are around the neurocognitive effects of the drugs and whether they may also cause cataracts and type 2 diabetes. In the pre-approval studies, there were more strokes among the patients taking the PCSK9 inhibitors, compared to placebo. There is good reason that in the US insurance companies and pharmacy benefit companies are restricting the use of these drugs. Not only are they costly, but they could possibly be less safe than the alternatives. They typically require a patient to have tried at least two statins and ezetimibe – a statin ‘booster’ – before considering a PCSK9 inhibitor.

4. There are alternatives: For many, statins “work.” Some commentators have argued that PCSK9s will never be mass market drugs like statins. Statins are now generically available, tolerable to many people and easily available. Plus, you don’t have to get an injection with a statin. Unless there is some serious science discrediting the statins, they may remain the king of the cholesterol-lowering world for a long time yet.

5. Market forces and prescribing habits seem to be working against these new drugs: Since they were introduced in the US and the UK, uptake has been very slow, not even reaching a quarter of analysts’ projections. Added to this are skeptical clinicians who are not all (yet) convinced of the overall benefits and safety of these more difficult to administer treatments. You can imagine the PR world is working on that particular problem. Doctors have been fooled in the past due to the frequent exaggeration around the benefits of statins and the downplaying of the risks, so maybe they’re more cynical this time around.

6. Sticker shock: Governments, insurers and others have been dragging their heels due to the sticker shock. In Canada, the annual price tag for the PCSK9s will probably range from $8,000 to $11,000 compared to the annual statin bill which is somewhere between $90 and $1,400 in BC. In the UK, the National Institute for Health and Care Excellence (NICE), which appraises new medicines and health technologies initially rejected both PCSK9s. They have now approved evolocumab. In the US, the New England Comparative Effectiveness Public Advisory Council said the PCSK9s were “effective but overpriced.”

One wonders what is happening in BC and whether or not these drugs will be approved for coverage and prescribed by our doctors?

Those are both good questions and seeing as we’ve got a new government coming in, we have lots of opportunity to improve drug coverage decisions. The BC Ministry of Health recently sent out a notice requesting “Public Input into PharmaCare Drug Coverage reviews,” adding that “the Ministry of Health is considering evolocumab (brand name, Repatha) for coverage.

BC’s Drug Review Process, however, is not perfect. Right now, our Drug Benefit Council (DBC) gives advice to the Ministry. The DBC looks at research around the drugs, consulting the national Common Drug Review (CDR) as well as considering if the drug represents “good value for the people of BC.” They tend to collect input from doctors, patients, caregivers, patient groups and the manufacturers and use this information to make coverage decisions.

There are a million ways for the pharmaceutical manufacturers to insert themselves into the process. They will want the government to spend our money on these new drugs. Other more sober voices, including mine, would say we need to study them more and decide if they represent good value.

BC has a chance to be wise, to resist the lobbying and PR efforts designed to spend money on drugs like this. Our new government is going to be surrounded by lobbyists representing companies that make such drugs. We hope they will be wise and not fall prey to all the PR tricks used to spend our money on questionable forms of healthcare.

Alan Cassels is a writer and former drug policy researcher. His latest book is The Cochrane Collaboration: Medicine’s Best Kept Secret. @AKECassels

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