Yves here. This post should serve as a huge red flag as to the low standards for FDA drug approvals as far as efficacy is concerned, as well as the willingness of major media outlets to run Big Pharma PR.
By Roy Poses, MD, Clinical Associate Professor of Medicine at Brown University, and the President of FIRM – the Foundation for Integrity and Responsibility in Medicine. Cross posted from the Health Care Renewal website
Here we go again. The same month that it approved Entresto (look here), the US Food and Drug Administration approved a new PCSK9 inhibitor cholesterol lowering agent, alirocumab, immediately marketed as the pricy Praluent by Sanofi and Regeneron, and heralded by a blast of media hype. Yet the evidence that this drug benefits patients is lacking, and critical review of the one big published randomized controlled trial of it raises many concerns.
Let us first consider the media hype. The TIME coverage started with this headline,
This New FDA-Approved Cholesterol Drug is a Game Changer
The New York Times article by Andrew Pollack quoted Katherine Wilemon, founder and president of the FH foundation, an advocacy group for patients with familial hypercholesterolemia, who have very high cholesterol values and increased risk of heart and vascular disease,
It represents a new era of hope for us.
The Washington Post article started with,
The Food and Drug Administration on Friday approved the first in a new class of cholesterol-busting drugs that many doctors believe will trigger a breakthrough in reducing the incidence of strokes and heart attacks, which kill hundreds of thousands of Americans each year.
The drugs are predicted to be blockbusters many times over, adding billions of dollars to prescription drug costs, said Steve Miller, senior vice president and chief medical officer at Express Scripts, a leading pharmacy benefit manager.
Another NY Times article by Gina Kolata directly described the drug as
powerful almost beyond belief.
Ms Colata also quoted a cardiologist who characterized the drug again as a “game changer.”
To be fair, note that while the WaPo article, NYT article by Pollack and the USA Today article provided hype attributed to “doctors,” or identified individuals, they also quoted some people who were very skeptical about the drug. However, in most of the media coverage, the positivity seemed to be more prominent and extreme than the skepticism.
The High Price
In general, the media coverage noted that the “breakthrough,” “blockbuster,” “powerful” new drug would not come cheap. Praluent would cost about $14,600 a year. Naturally, those selling it saw this as a bargain. For example, Andrew Pollack wrote in the NYT,
Sanofi and Regeneron Pharmaceuticals, which developed the product, said the price was justified by the potential benefits to patients and savings to the health care system that the drug would provide by preventing heart attacks and strokes — though the ability of the drug to do that has not been proved.
‘We came to a price that is reflective of value, not what the market will bear,’ said Elias Zerhouni, head of research and development at Sanofi, who said his own brother had suffered three heart attacks and needed new options to control cholesterol.
Gina Kolata went farther,
The $14,600 yearly price of the drug, which is injected under the skin once every two weeks, is a stunner. Yet for some patients, that might actually be a bargain.
She justified this by comparing the cost to apheresis, a radical procedure to treat high cholesterol. She did not discuss whether it had any evidence of clinical benefit. Yet,
‘Cost is in the eye of the beholder,‘ said Dr. Daniel Soffer, [Mr. DeRuchie’s cardiologist at the University of Pennsylvania.
Presumably, Dr Soffer was the one who had recommended the apheresis treatment.
Note that at best, the company that sells this drug can justify the price only in terms of potential, not actual value or results.
No Evidence for Clinical Benefit
Praluent, generic name alirocumb, is certainly a breakthrough in that it seeks to lower cholesterol through a novel mechanism. The drug is a biologic, a monoclonal antibody that inhibits the enzyme PCSK9.
Yet a close reading of the one large published randomized controlled trial of alirocumab(1) belays the hype beyond that. The study by Robinson et al was a double blind randomized controlled trial of alirocumab injections every 2 weeks versus placebo. The protocol called for patients to be treated for 78 weeks, and followed for 8 more weeks, a bit more than one and one-half years.
Loss to Follow Up and Missing Data
The study enrolled 1553 patients in the alirocumab group, and 788 in the placebo group. However, many patients did not complete the study: a total of 437 (28.1%) in the alirocumab group, and 193 (24.5% in the placebo group). Reasons for noncompletion were adverse events (113, 7.2% alirocumab vs 47, 6.0% placebo); “nonadherent” to treatment (60, 3.9% vs 38, 4.7%), and “other reason,” (264, 17.0% vs 108, 13.7%).
So the drop out rate was fairly high. It was particularly troubling that the reasons for most of the drop outs were vague “other reaons.” I could not find a clarification of this term in the main article or supplemental materials.
Furthermore, it was not clear how the investigators intended to collect data from patients after they dropped out, and how complete data collection about clinical events was for patients who dropped out. (Note that for patients that dropped out, the investigators simply imputed, that is estimated cholesterol values, but did not necessarily measure them. So even this measure was “potential.”)
Drop outs and missing data are classically problematic because patients may drop out after suffering events that could be counted as study outcomes. The rate of these events could differ according to treatment group. If patients who dropped out of the alirocumab group had more adverse events than those who dropped out of the placebo group, and these events were not recorded, the high drop out rate could have concealed important harms of the drug.
Thus it is quite possible that the study by Robinson et al undercounted adverse events due to aliromucab.
Multiple Study Sites
The study enrolled patients at a remarkable number of sites, 320 in 27 countries, so that the average number of patients enrolled per site was only seven. It seems improbable that a study involving so many investigators and centers, most of whom must have devoted little of their time and effort to this particular study, would have adequate quality control. I could not find a discussion of implementation quality control in the published article.
Thus it is possible that poor quality of study implementation, which could have affected enrollment and data collection, may have challenged the validity of the Robinson et al study.
Lack of Generalizability in the Patient Population
The complete list of exclusion criteria, only appearing in the supplementary material, was extensive. Patients with many common problems were supposed to be excluded, and the definition of the some exclusion criteria were vague and subjective.
Common conditions leading to exclusion were:
– Recent heart and cardiovascular problems, i.e., “(within 3 months prior to the screening visit [Week -3] or between screening and randomization visits) MI, unstable angina leading to hospitalization, uncontrolled cardiac arrhythmia, CABG, PCI, carotid surgery or stenting, cerebrovascular accident, transient ischemic attack, endovascular procedure or surgical intervention for peripheral vascular disease.”
– “Planned to undergo scheduled PCI, CABG, carotid or peripheral revascularization during the study”
– Severe congestive heart failure, i.e., “New York Heart Association Class III or IV heart failure within the past 12 months”
– Poorly controlled hypertension, i.e., “Systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg at screening visit or randomization visit.”
– “History of hemorrhagic stroke.”
– “History of active optic nerve disease.”
– Use of systemic corticosteroids, other than for replacement
– “History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer.”
– “History of HIV positivity.”
– “Positive test for Hepatitis B surface antigen and/or Hepatitis C antibody (confirmed by reflexive testing).”
– Kidney dysfunction, specifically, “eGFR <30 nbsp=”” p=””>- Poorly controlled diabetes, specifically, HbA1c >10%.
– Abnormal liver enzymes, specifically, ALT or AST > x ULN
Vaguely described exclusions were:
E 25. Conditions/situations such as:
A) Any clinically significant abnormality identified at the time of screening that in the
judgment of the Investigator or any sub-Investigator would preclude safe completion
of the study or constrain endpoints assessment such as major systemic diseases,
patients with short life expectancy.
B) Patients considered by the Investigator or any sub-Investigator as inappropriate
for this study for any reason, e.g.:
i) Those deemed unable to meet specific protocol requirements, such as scheduled
ii) Those deemed unable to administer or tolerate long-term injections as per the
patient or the investigator.
iv) Presence of any other conditions (eg, geographic, social….) actual or anticipated,
that the Investigator feels would restrict or limit the patient’s participation for the
duration of the study.
Thus the study would have excluded patients with a variety of common conditions, and may have excluded many other patients based on rather poorly defined decisions by individual investigators. Since patients in clinical practice commonly have common conditions, the generalizability of the results of this study to many practices and patients was not clear.
No Evidence of Clinical Benefit
Patients should not be subject to treatments whose benefits do not clearly outweigh their harms. The Robinson et al article focused on reductions in measured cholesterol, particularly LDL cholesterol. The new drug certainly did seem to clearl reduce cholesterol, particularly LDL cholesterol. However, these are only the results of laboratory tests.
Although high cholesterol and high LDL cholesterol indicate increased risk of future cardiac events, many patients with abnormal values do not have such events. Having a high cholesterol or LDL cholesterol does not directly cause symptoms, or dysfunction. Thus simply lowering cholesterol does not immediately or directly benefit patients. Furthermore, other drug have been shown to lower cholesterol, but ultimately they accomplished this without ever being shown to benefit patients, e.g., by preventing heart attacks, strokes, or premature death.
However, cholesterol values are considered intermediate or surrogate variables. They are not directly related to what happens to patients, who they feel or function, whether they get new diseases, or when they die. So only showing that the new drug lowers cholesterol does not prove clinical patient benefit.
Although the published trial did attempt to record cardiovascular events, it did not find that the drug prevented them. The small difference in total cardiovascular events affecting patients given alirocumab (4.6%) versus placebo (5.1%) did not reach statistical significance, that is, could well have been due to chance alone.
Furthermore, while elevated cholesterol is a chronic problem, and the problems with which it is correlated occur over the long run, the study ran for less than 2 years. It could not measure the effects of the new drug beyond that.
So the clinical benefit of the drug was not evident in this trial.
On the other hand, the drug was not without its own risks. More patients who received aliromucab left the study due to adverse events (7.2%) thand did those who got placebo (5.8%), as noted above. Also, as noted above, it was possible that adverse events affecting dropouts were not fully recorded. Given that there were higher rates of dropouts due to non adherence and “other” reasons among patients who received alirocumab, the study might still have missed important adverse effects of the new drug.
So the study did not prove that the new drug has any clinical benefits, showed it does have clinical harms, and could still have easily underestimated its harms. So it certainly did not show it had benefits that outweighed its harms.
Summary and Conclusions
The NEJM study was accompanied by an editorial by Stone and Lloyd-Jones(2) which documented that drugs previously shown to lower cholesterol were never proved to do any good for patients, and concluded,
it would be premature to endorse these drugs for widespread use before the ongoing randomized trials, appropriately powered for primary end-point analysis and safety assessment, are available.
After an FDA advisory committee recommended approval of aliromucab in June, 2015, John Mandrola entitled a Medscape article,
Dear FDA: Resist the Urge on PCSK9 Drugs
His reasons included lack of proof of clinical benefits, and concerns that harms may have been missed but mainly because of its inability to detect long-term outcomes.
Again, the current media articles also noted the concerns raised by Dr Mandrola and the NEJM editorial These concerns, however, did not dissuade the FDA from approving aliromucab. These concerns did not apparently affect the pricing of Praluent. These concerns will likely not deter the drug manufacturers from continuing an aggressive marketing campaign. Whether these concerns will deter physicians from prescribing, or patients from asking for these drugs is unknown, but unlikely.
And I have not seen anything published so far that addressed how the problem with dropouts and missing data may have lead to further underestimation of aliromucab’s harms, the multiplicity of study sites may have lead to quality control problems further challenging the study’s validity, and the extensive exclusion criteria may have reduced the study’s generalizability.
So here we go again. Another new drug is put on the market accompanied by a mighty hoopla, yet in the absence of clear data that it does more good for patients than harm.
As we said last year about valsartan-sacubitril, also just (July, 2015) put on the market as Entresto, at a high price and with lots of hype,…
All the enthusiasm about this drug may be premature, and does not appear to be evidence-based. That clinical research sponsored by organizations that sell health care goods and services may be manipulated to make the sponsors’ products look better than they really are is now an old story. We have seen multiple instances in which drugs and devices turned out to be less efficacious and/or more dangerous than originally advertised. Excess enthusiasm about such new innovations may drive up costs, and worse, hurt patients. Physicians, other health care professionals, and those concerned about health policy ought to be much more skeptical about every new instance of a purportedly wondrous innovation.
Evidence-based medicine rigorously applied suggests that individual health care and health policy decisions should be driven by the best available evidence, mostly from clinical research, about the benefits and harms of tests, treatments, programs, and so on, in the context of what outcomes matter to patients. The skepticism EBM should engender could lead to health care that is more about patients and their outcomes, and less about ideology, hype, and hucksterism.
How high must our health care costs go, and how many unproven treatments must eventually be exposed as such before we learn that lesson?
See original post for references. Comments enabled at the request of the author
According to the study, the drug does what it’s supposed to do. That is if you’re in the mood to trust their data and methods.
So your objection is really to the hype. You object to the hype and have questions about what is actually accomplished by the taking of the drug in relation to its price and lack of long term testing.
If you’ve ever flipped through a Time magazine or looked at an ny times, you’ve seen page after page of pharma ads. I would guess that this is the real explanation for the endless loop of hype for new drugs, and the big empty space where the airing of reasoned objections, like yours, would be.
Actually, it is not known yet whether the drug does what it’s supposed to do. What it’s supposed to do is lower the risk of cardiovascular events and (hopefully) death, with acceptable safety. The trials that have been completed so far were designed to measure the drug’s effect on LDL-cholesterol and to provide some preliminary safety data. The sponsors are running a large cardiovascular outcomes trial that will not be completed for a couple of years. Until that data is available, it is not possible to really know how effective the drug is in reducing the risk of heart attack, stroke, death, etc., and how safe the drug is.
I meant that in a very specific way, the drug did lower cholesterol and LDL cholesterol, not that it worked to lower cardiovascular events. I was only attempting to isolate the cause of big outlets reporting past true conclusions.
This article makes no mention of the neurocognitive adverse events because. PCSK9 controls nerve cell proliferation, which I think might be the “other” reasons why people dropped out.
“Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.”
The only people I could see PCSK9 inhibitors helping are people with single nucleotide polymorphisms in their PCSK9 genes and even then I would only suggest that they lower calcium intake (Calcium is a cofactor for the PCSK9 enzyme) or live a healthier lifestyle to reduce the free radicals that promote inflammation.
Also, herbs that contain berberine, such as Goldenseal Root are natural PCSK9 inhibitors.
The real reason I hate these drugs because they are only curing lifestyle diseases. If they spent that $15,000 on better food they would be better off in so many other areas as well.
I have heart disease in my family, mothers 1st heart surgery was at 53, one brother died at 48 from heart disease, and my other brother has a triple bypass at 50, and all our cholesterol levels are high LDL, low HDL. I am 50 and credit my lack of heart disease to keeping my inflammation and oxidative damage down, the others in my family did not (smoking, red meat, over eating). I do not care that my cholesterol is high as I think it serves a purpose. It is just that since my family trait is that we make more LDL, that it can cause trouble when we have too much inflammation.
Berberine and Vitamin C it is then. Berberine is $5/month at Swanson Vitamins on the net. It also has some clinical evidence of effectiveness if you’re pre-diabetic. Plus hit the treadmill – hup-hup – and make believe you like it.
I want any lawyers in the house to draw up either an Executive Order or Constitution Amendment – which ever you are more comfortable with – which makes wonder drugs illegal and also puts statins on probation until efficacy is proven AND they are priced the same as aspirin. No more of this “How much is your life worth” pricing. What a bunch of shit that is. You can’t put in slow, protracted death costs in the price either – that’s too incestuous under our current healthcare system. Until we get the statin puzzle figured out, we will recommend Berberine and Vitamin C.
Mail it to Obama and tell him to sign the damn thing.
fda = financial dispensary association
great piece on how little we mean to those who insist on making their numbers on the 13 th week and getting what they want at any price to humanity…
as to advertising model leading to this sad reflection on editorial content…google made its fortune on converting the late nite tv pay per inquiry business into cashflow…seems the advertising sales staff need a hand in finding a new way of bringing in revenue without the need to squeeze in two pages of disclosures in type size so small one might as well use steganography tools to decipher it…
Putting aside the question of does lowering cholesterol really have anything to do with heart attack and stroke risk, which seems like the core question to answer for old and new drugs, I was curious what the percent cholesterol reduction is for the new wonder drug?
If memory serves, existing statins (which shouldn’t cost more than aspirin, in my worthless opinion.) are on the order of 30-50% reduction in total cholesterol. Or maybe in just LDL – I can’t remember.
Additionally, recently we’ve been hearing opinions, which I believe come from the dairy and red meat industrial complex, and supported by medical opinion from some medical professionals, that high cholesterol foods don’t matter much because only 25% of your cholesterol comes from food and the rest is made in the body.
So now I’m wondering if the new cost of America’s eggs and bacon breakfast at Denny’s (or wherever) should really be calculated as so:
$15,000/yr [wonder drug] + biweekly cost of going to the clinic for injections + doctor oversight + $7 plus tip for breakfast.
I’m asking because I really don’t know the answer, and that troubles me.
I don’t know the answer either, and I am no expert. Nor do I have links. I have heard and read that allegedly “new studies” show that it’s not about eating foods with a high(er) cholesterol count that causes cholesterol issues for the eater. Rather it’s the amount of saturated fat that you eat that allegedly causes your cholesterol levels (whether LDL, HDL or whatever, I don’t know) to rise. Saturated fats are those that are solid at room temps, and most packaging of processed foods will tell you how much saturated fat is contained in them.
I think one thing anyone can do is attempt to eat a healthy diet focused on fruits, veggies, whole grains and keep your intake of animals and animal products (dairy) at a lower level. Avoid processed foods, as best you can.
My goal is to avoid taking any drugs for heart issues, if at all possible. My family has a history of heart issues, and my parents took statins and other heart meds for years. I am well within the age range that they started taking these drugs, and my blood work comes up great with no need for drugs. Why? Well I work out regularly, and I eat a really healthy diet. Neither of my parents could say the same thing.
Avoid drugs, if at all possible, is a good rule of thumb. We can no longer rely on the FDA to be honest with us about the value or effects of these drugs.
Yes, I think the cost of a years’s supply of broccoli, tomatoes, blueberries, avocados, spinach, and oatmeal is a bit less than $15,000!
From the post…” We have seen multiple instances in which drugs and devices turned out to be less efficacious and/or more dangerous than originally advertised. Excess enthusiasm about such new innovations may drive up costs, and worse, hurt patients.”
This is a critical point, in my weekend warrior days i was regularly offered vioxx as a “better” alternative to ibuprofen, and even that wonder drug is causing me concern now…better go hit the yoga mat before work.
Why hasn’t my comment appeared?
“I speak to maps. And sometimes they something back to me.”
I guess I do not get what puts my comments in the moderation queue, since my comment on why my other comment was not published was published.
I’ve found that if I include one or more links, I increase the likelihood of moderation. Since I often do include links as a convenience to readers, I accept that some of my comments will be delayed. There are probably various words that are frequently used in advertisements that will nudge a comment towards the moderation queue. It’s just something that we live with here in the wild and woolly internet.
The mysteries of Akismet are beyond knowing.
American medical “care” has gone completely off the rails…..from MRI to these drugs to the fact that 50% of surgeries are unnecessary….and no one wants to tell the truth. The only solution is to put all doctors on salary. Leave them alone and let them determine what works. And make the system ignore what patients want. That way the doctors, those who went to medical school, can make a decision as to what is worth doing and what is not worth doing without any concern regarding outside factors or pressures. If a medicine is helpful doctors will start to use it. If it is not worth the trouble they won’t. If a surgery will help they will do it. If it is more likely to be a waste of time they won’t. Long before Medicare that is how surgeons worked. They chose the patients they could help and operated, and those they thought would not be helped they did not. Since there was a relative shortage of surgeons they could pick and choose. Textbooks were written outlining indications and complications. A surgeon did surgery at his peril is the outcome was predictably poor. Now all a surgeon needs is cover by an MRI report, insurance and a level of greed or patient or hospital pressure to operate. Until the society gets over its irrational fear that if doctors are paid without regard to how hard they work or how many units they produce that they might take a day off and play golf we are going to suffer. We do not complain and burn down buildings when firemen sit at the firehouse playing cards or watching videos. Would we really complain if doctors did not do things to patients who don’t need something done to them?
Most people don’t pay much attention to their health. They want their doctor to tell them what to do or they definitely want a pill or similar to “fix” things. We are way over-medicated in this country, but its mainly because people can’t be bothered to find alternate solutions. Solutions can include eating a healthier diet, exercising, enduring small amounts of pain, and so on.
BigPharma, however, spends a lot of money advertising in all of the media, whereby, they encourage consumers to ASK for drugs from their doctors. It amazes me. My goal is to avoid drugs at all costs, unless totally necessary. It appears, though, that a high percentage of citizens prefer to take drugs without question.
Arson is a crime. PR for a trumped up drug that costs a bundle is considered good marketing. If there were a way to make arson profitable, I’ll bet we’d have a lot more fires to keep those firemen busy. And of course, once they got busy, you would then need firehouse administrators. You’d probably need bigger and better firehouses. Maybe even a national firehouse electronic record so that big data could mine for fire research. Your employer would start offering fire insurance plans – and the free market would let you decide which fire plan was best for your family.
Based on everything above, this seems more of a Stage II trial than a final trial prior to general approval. It is certainly appropriate in early stages to restrict your subject pool to determine if the drug does what it is supposed to do and if there are any clearly drug-associated side effects. Too much noise makes it impossible to separate adverse drug events from general adverse events that would occur anyway.
As a measure of lowering LDL it would seem to do that but, as well addressed above, that alone may not be enough to do what is intended: reduce cardiovascular events. As with the other drugs that do lower cholesterol levels but still don’t seem to prevent the final events they are targeted after, it still comes off that there is merely a correlation between cholesterol level and cardiovascular risk but no proof that the higher cholesterol level CAUSES the events. Perhaps high cholesterol level is a parallel effect along WITH cardiovascular event.
It is pretty clear that if you reduce cholesterol to low/normal levels and yet STILL see a higher prevalence of cardiovascular events in those patients, that it isn’t the cholesterol itself that is the ultimate cause, it may just be a side player.
“PRALUENT … Lowers cholesterol as effectively as Placebo!!!”
I’m a cardiologist with inherited familial heterozygous hypercholesteremia. Heart attack age 44. Bypass age 50. Carotid surgery age 51. Since then been on the plane twice a month to fly to an LDL apheresis center, for years.
Just offered a chance to participate in a 3 month study getting twice monthly injections of this same drug with a 33% chance of getting placebo injections. I jumped at the chance. First injection just a few minutes ago. Drug lowers LDL about as well as the machine but result more durable.
I’m well aware after nearly 25 years of practice the limitations of knowledge. Many things we did as a resident are now considered useless or even dangerous for treatment of heart disease, becoming apparent only with time. Look at the trials at raising good HDL cholesterol for example. Sometimes what seems obviously beneficial is in fact not.
I also agree the medical system is broken, that there is often too much incentive to do procedures and treat, that Pharma has too much power and tries to influence our decisions in too many ways. The FDA may be influenced but over the years they catch flak for being too slow too, and we’re always a year or two behind Europe for approvals. And your salaried doctor…well, you won’t be overtreated, that much I can say with great certainty. Studies are never completely “real world”. Their design is always criticized, limitations always pointed out. Lists of exclusionary criteria are always a mile long and they have their reasons, one of which is to prevent people from dying of something else during the study. As far as diet goes, it’s not going to do a thing when the disease is strongly inherited, particularly the doubly inherited patients with total cholesterol in the 600, 800, and above 1000 range. Dead before 40. This is not a drug for people who can jog down their total chol of 200 into the normal range.
I hate big pharma’s influence and approach, have for years. But while trying every statin made over 30+ years, unable to tolerate even small amounts, I looked at those little plastic pill cans in quiet desperation and said, “I literally can’t take this drug to save my life”. I took a picture of the first injection vial I got this morning this morning.
This drug was approved early in part because there are no good options for statin-resistant patients except the machine. The FDA limited its use to secondary prevention only; we all know the company wanted the much bigger primary market. And believe me, they are right about the costs of pheresis. My insurance company pays nearly $14,000 per month….not per year like this drug…to send me here. Flight costs to me are more, then add taxi, meals.
This is a fabulous web site with intelligent discourse. But IMO you’re barking up the wrong cynical tree here. If something disturbing surfaces later, I may one day regret taking this medicine. But I really doubt it.
@ Alan: But that is the problem here – patients like you DO benefit from this particular treatment, and even at $14,000 a year, it IS a cheaper alternative for YOU. However, BigPharma isn’t satisfied with selling this MAB to a few hundred/thousand patients who would actually benefit … they would never recover their costs. Hence the hype and the attempt to market it to a more general population. IF the FDA would label it restrictively to hypercholesteremia patients, that would be fine. But you can bet the suits at BigPharma would scream at the top of their lungs.
I agree. But at 20 to 40% of patients who can’t tolerate a statin, but would benefit, it is still a substantial number.
Another aspect: industry sponsored drug trials tend to bury side effects and intolerance…perhaps “withdrawn for other reasons” as pointed out; I think they did so with statin studies, so likely have a larger pool of pts who definitely could benefit from them but can’t take them. I see them in my practice frequently. This would be the substitute drug if longer term studies are positive. It could be more than you think.
Just to re-iterate I hate what Pharma is getting away with. For example Valeant just bought the market of a drug I use 2 or 3 times a day called Isuprel, and immediately raised the price from about $50 to 1200. Been $50 forever. I hate the ba$#*+ds.
And they are so good at manipulating us. One survey of doctors found that 85% of us think our colleagues are manipulated by industry, but only 15% think they themselves are.
But this drug fills an important hole. Apparently took 10 years to come up with.
It’s the wrong target for pointing out big pharma abuse.
Is labelled only for FH intolerant of statins, only for secondary prevention of further events. That’s all they got for now anyway
@Chris B: based on my own experience, including a link in one’s comment greatly increases the odds of it getting diverted into the mod queue. More than 1 link almost guarantees it. Now that your OP has appeared – yep, 5 links. Best you can hope in such cases is that time between posting and mod approval is not so long as to render the post effectively irrelevant, but as Yves frequently notes, this site is run by all of 1.3 people.
Several years ago I participated in the care of a patient with familial hypercholesterolemia, as medical director of a pheresis unit in the blood bank of a teaching hospital. The patient was a late-teen female with a rare homozygous condition involving one of the related genes (LDLR iirc). Her serum cholesterol values were sky high of course, but the scary finding was large subcutaneous nodules on the back of her elbows. After a year or so, the nodules went from firm to rubbery and were noticeably smaller, suggesting that we were getting ahead of the disease process. The serum cholesterol values declined as well. Her family moved to another city after a few years, so I don’t have a long term followup.
Did it help her? I’m inclined to think so, because the shrinkage of the nodules suggested net removal of the total body cholesterol burden. But absent a long-term study, we can’t be sure.
We should cut Robinson et al. some slack. They had to assemble data from hundreds of sites because the disease is so rare, probably high hundreds to low thousands for the US pop. And they had to use serum cholesterol values as a measure of efficacy because measuring the real end points (strokes and heart attacks) would require following the patients 10-20 years.
There’s ample precedent for using serum cholesterol values as surrogates for clinical outcomes. The first drugs for lowering serum cholesterol were marketed with only that claim. Everyone knew they were for vascular complications of high cholesterol, but the drug companies didn’t have to do long trials. Some of them turned out to be ineffective, so the FDA should have required long-term followup. But the decision was reasonable in light of what was known at the time.
What looks way out of line here is the suggestion that this drug will be useful for patients without this specific genetic cause of hypercholesterolemia (>99% of patients). All the talk about “breakthrough” and “game changer” is journalistic malpractice unless it’s carefully qualified to state that only a small population of patients are known to benefit, based on preset evidence. It will be great if other patients are helped, but it’s premature to go all hopey-changy on the pages of the NYT.
‘ The great cholesterol myth’
Author Steven Sinatra
Read it then you r no longer urinating into the wind!
I agree with Roy Poses that the risks and benefits of PCSK9 inhibitors will not be well-defined until adequately powered cardiovascular outcomes trials are completed. Fortunately, such trials are underway, so we should have some results in the next few years. Until then, these drugs should not be widely used in my opinion. In case anyone is interested, I have discussed PCSK9 inhibitors on my blog:
I have been following these drugs because members of my family have familial hypercholesterolemia (FH), although they are not in need of an additional drug at the present time. I attended the FDA advisory committee meetings on alirocumab and evolocumab. I can understand why some people might want to start taking this drug now even though the data are not all in, but I think the drug should only be used in a limited number of people until the outcomes trials are completed.
There are unanswered questions, including whether very low levels of LDL are safe in the long-term, whether the drugs increase the risk of developing diabetes, whether the drugs increase the risk of memory impairment or other neurocognitive events, and so on. Until the outcomes trials are completed, we just don’t know how safe and effective these drugs are.
In the meantime, most people are able to lower their cholesterol with a statin and/or with ezetimibe and/or a bile acid sequestrant.
Physicians, other health care professionals, and those concerned about health policy ought to be much more skeptical about every new instance of a purportedly wondrous innovation. The skepticism EBM should engender could lead to health care that is more about patients and their outcomes, and less about ideology, hype, and hucksterism.