For the past year a large contingent of concerned doctors and medical groups inveighed against the FDA’s preliminary decision to approve the new drug Leqembi for early dementia. Given intravenously at a cost of $25,000 a year, the drug is purported to slow the deposition of plaques in the brain, something that is seen often in people with Alzheimer’s dementia. But does it slow dementia, help cognition, or have any clinical benefit? And are the plaques of any significance or are they a residual of the dementia process, or even a protective means of compensation? That we don’t know. Similar to other clinically useless drugs like Aricept and Exelon, this drug does slightly improve a memory test score in a small number of selected users for a brief period of time when compared to placebo, but that’s it. Based on a tainted study that was brief in duration and both financed by and designed by the drug company that makes Leqembi, the FDA approved the drug 6-0, and Medicare agreed to pay the whooping price tag.
Leqembi’s approval is indicative of how the pharmaceutical industry has steered research and medicine use in a very dangerous direction. Many have written about this, and I encourage everyone to read Vinay Prasad’s book Ending Medical Reversals which is a commonsense explanation both of how drug companies and academic medical centers can twist studies to prove benefit fallaciously, and also how you as a consumer of health care can best assess if a new drug is best for you. In addition, John Abramson from Harvard wrote a recent brief article about this, and in our videos we have some wonderful examples about how to assess medical evidence.
Dementia is a cascade of brain cell death. No one is quite sure what instigates the process or how to stop it. Depending on where in the brain the majority of cells die will define the nature of dementia. Frontal lobe dementia typically provokes poor judgment and rash behavior; temporal lobe involvement causes delusions and hallucinations and paranoia; involvement near the basal ganglia will lead to parkinsonian symptoms. But all dementia is manifested by more than just memory loss, which itself is normal as we age. People with dementia exhibit cognitive decline whereby their brains cannot process information well thus leading to aberrant behavior and a severe impairment of thinking and reasoning. The extent of dementia, the speed at which it progresses, and the precise symptomatology vary from person to person and are not well defined or understood.
Can we slow or mitigate the process, or can we stop it or even prevent it? Given that we don’t know the etiology of cell death, or why people are struck in different parts of their brains, the answer is no. We do know that people who exercise regularly, don’t smoke, meditate or alleviate stress in other ways, and who eat a low-processed flour/sugar diet with a lot of fiber and fruits and vegetables both have a marked reduced chance of developing dementia and, if they do have it, progress more slowly. We have described this in our videos both under memory loss and nutrition.
If we don’t know what causes it, then how can we medically treat it? The answer is, we can’t, but that hasn’t stopped the pharmaceutical industry and its very compliant doctors from passing out snake oils to desperate people and claiming benefits while reaping huge profits. The dementia drug industry earns tens of billions of dollars annually for drug companies, buttresses neurologists claim to be treating a disease that has no treatment and provides people with false hope and dashed dreams. Now with Leqembi the price tag will invariably escalate because this expensive and likely worthless (and harmful) drug will be doled out by doctors who seek to please their patients with fallacious claims of miracle cures and it will be gladly taken by people suffering from dementia, and their families, because it is a ray of hope in a dark sky.
Let’s look at one of the earliest dementia drugs to show how the drug companies create illusory potions and market them to doctors and patients through deceptive advertising that objurgates their inherent risks and feckless actions. Aricept is one of the first of these snake oils, and its history is illustrative of how drug companies study, market, and dispense medicines of low value and high risk at the tune of tens of billions of dollars of annual profits.
When Aricept (Donepezil) first was introduced it was slated to alter brain chemicals in a way that slowed the progression of dementia and alleviated some of the most frustrating manifestations of the disease, primarily foggy thinking and memory loss. The barometer of success (given that there is no objective means of measuring drug impact, especially whether it slows progression) is caregiver score, whereby patients and their caregivers are asked if they are doing better on the drug. In some of the earliest studies, 30% of people taking this drug reported some degree of improvement during the trial’s brief duration. That sounds pretty good!
But wait, how much improvement, and improvement in what? That was never defined. Nor was the duration of improvement. But more fundamentally, when compared to placebo, the drug did nothing. It turns out that 30% of people receiving placebo also claimed to be better! Thus the entire effect of this expensive drug was that it had a robust placebo effect.
So, the drug companies got down to business. Such companies typically carry out small studies they never publish to ascertain means of demonstrating a manipulated improvement from their product. They sift through various useless means of assessing dementia, alter the people they are treating to find the “ideal” group that shows benefit and does not show harm, and use statistical wizardly to magnify tiny benefits into big ones, while carrying out the studies for as long as this mythical benefit is present but not a day longer. Most drug company studies are not published at all; only those that show benefit make it into the major journals. The complaint academic doctors who carry out these studies, and whose institutions and ultimately themselves are paid well for doing the bidding of drug companies, take their marching orders from the companies themselves as to how the study must be done. In fact, the vast majority of financing of academic medical centers and their physicians derives from drug-company largesse in carrying out large studies, thus dissuading any such doctors and institutions from doing anything short of towing the company line lest the funding migrate to other institutions and other doctors.
Rather than trying to help people, or proving the lack of efficacy of drugs, these academic lackies and their pharmaceutical handlers are most concerned with twisting reality in a way that makes the drugs look good. And with Aricept they found a way. They invented a 70 questions memory test and, with no basis for this other than to fit their model, ascertained that a 4-point improvement in this test score indicated true clinical benefit. With Aricept, 9% of people taking it improved by 4 points compared to placebo, most of the benefit occurring three months after the drug’s initiation, peaking at 6 months, and by 12 months placebo and drug patients score the same on the test. This tiny and largely symbolic improvement is then magnified through statistics (see our videos as to how this is done) to claim a 20% improvement with the drug. That the improvement is clinically insignificant, that it impacts a tiny number of patients, that it is totally erased in a year; those are not mentioned in the study. In fact, every dementia study ends in a year (I wonder why!) when placebo starts to overtake the drug, and friends of mine in NIH state (although I can’t verify) state that after a year the small unpublished studies demonstrate that placebo does better than drug. You won’t see those studies! And thus is Aricept and its cousins like Exelon, promoted mostly by neurologists as being an effective dementia drug, and most such doctors continue to prescribe the drugs for years and years, likely harming their patients over the long run.
Deception about benefit is one thing, but blindness to risk is another. In fact, one can argue (as I have) that to prescribe a medicine based on tainted and manicured drug-company data that has no clinical benefit and has potential risk is a violation of the Hippocratic Oath of FIRST DO NO HARM, but such stipulations rarely stand in the way of doctors who like to drug their patients and sew a promise of cure. If one wonders how a doctor, especially a specialist in the field, can dispense drugs like this and make false promises while denying risk clearly without actually reading or understanding the studies upon which they base their recommendations, well, welcome to American health care, where the drug companies have doctors on a very tight leash.
What are the risks? Most studies deliberately have excluded people most susceptible to risks, but they have become apparent as doctors pass out billions of dollars of these medicines, and most geriatric doctors like me consider these drugs among the riskiest to give to elders with memory loss. They include lack of appetite, weight loss, increased agitation, and less commonly heart block and passing out. Just what we don’t want in our patients with dementia! But it’s all good, because if you get one of those side effects there is a good chance your neurologist won’t stop the drug but will treat the side effects with other drugs, thus pushing you deep into the mud pit of polypharmacy!
Remember, 30% of people taking these drugs think they or their loved ones have improved based on a placebo effect, so many are willing to write off the side effects and the lack of genuine efficacy due to the false perception of benefit. The placebo effect works in reverse too; people who stop these drugs often feel they are worse, and I have had examples of patients’ families who believed we had stopped the drug and told us their mom is much worse when in fact they are still receiving the drug. Drug companies and their complaint doctors are very nimble at using placebo effects to boost the benefit of drugs while largely dismissing the side effects, and hence we have billions spent on a well-designed lie.
The new dementia miracle called Leqembi takes this formula to another level. This drug has been barely studied, and what study has been done has been financed and designed by drug companies, excluding anyone who could be harmed by vetting people before enrolling them. It’s a very brief study, and the only two improvements are a reduction in plaque—which as we have noted may not have any clinical meaning and may even be compensatory—and a slight improvement in the bogus test score. There is no proven clinical benefit at all, no proven slowing of disease, no improvement in memory or cognition beyond placebo, and no ability to ascertain long term effects. The side effect profile is far worse than even Aricept, with a litany of problems many of which are still poorly defined, but one of which is catastrophic and will clearly be far more common when the drug is introduced to the public: brain bleeding. Yes, this drug which reduces plaque and does nothing else can lead to life threatening stroke-provoking brain bleeds, and yet the FDA approved it 6-0 because the clever pharmaceutical company composers and their orchestra of compliant academic doctors have been sure to minimize this “tiny inconvenience” in their studies.
All that for $25,000 a year! Quite a deal!
So let’s summarize the problems with the Leqembi study and its approval:
It was designed and carried out by the drug company that made the drug, thus assuring that there is ample bias in patient selection, duration of treatment, and other factors to assure that the drug demonstrates benefit and shows minimal risk.
There are no clinical endpoints evaluated, which in this case would be: does the patient and/or caregiver notice an improvement. Rather the study uses surrogate markers: the elimination of plaque in the brain (which may not be the cause of dementia but rather a residual marker of damage or even protective) and improved manicured test scores.
The side effects are minimized, especially the very salient risk of severe and even deadly bleeding in the brain which this drug clearly causes, likely by tearing apart the plaque.
No long-term data is available nor are other studies.
Many doctors and medical news sources are claiming that the drug slows dementia down by 60%. Clearly, through the lens of science and common sense, there is no means of demonstrating how much a drug slows down a progressive disease, nor do we have any evidence beyond a short study that looks only at surrogate endpoints that the drug has any impact at all on dementia progression or symptoms. The 60% number is a classic statistical means of deception common in medical literature and oft cited by doctors and others who do not understand its derivation. At this point, we can’t say it slows down dementia at all. See our video on medical statistics to understand where this number came from and why it has no meaning or value.
The FDA drug approval process is financed 100% by pharmaceutical companies, so its unanimous approval in no way indicates it is effective or safe.
To subject yourself to a drug with so little evidence of efficacy and a huge risk of serious side effects is certainly unfounded, but many patients simply are told by their neurologists: A new drug is out that clearly works and received universal approval by the FDA, so want to try it? It’s expensive, but don’t worry, insurance will pay. Unless you can ask the right questions, you may be given poison with a promise of salvation. While neurologists in this country seem to want to prescribe the drug, those of us in geriatrics, and most doctors across the globe otherwise, have said a hard NO!
From cholesterol drugs to diabetes drugs to drugs slated to help you lose weight and think better and live longer, very few medicines pass muster once tough questions are asked. This is true for medical devices too, and Jeanne Lenzer’s book The Danger Within Us shows how the FDA fails us on that score as well. The fact that the drug is approved, that a select group of neurologists endorse it, and that Medicare will pay for it does not mean it works and will not harm you. It is indictive of how the process works: drug companies pay for and design studies to serve their interests, they pay the FDA to approve it while paying enough people in Congress to assure Medicare will finance it, and then a handful of doctors who simply read headlines and drug company pamphlets, or who are paid by these drug companies either directly or indirectly (by financing their research) eagerly hand them out.
You as a consumer of health care should be wary. It is always best to assure the questions we posed in Health Gems (July/August newsletter), and the process we describe in our video about how to evaluate medical data, steers you toward a position of skepticism, especially when a drug is new and barely tested in the real world. Time alone will tell if Leqembi will help anyone beyond improving some surrogate markers, and time will tell how many trusting souls it will maim or kill, but it’s best not to be in front of the line exposing your body and brain to something that is more likely than not to provide high profits for drug makers but hurt a lot of people along the way.