Cancer, Herpes, Metformin and the FDA

Three articles on medical breakthroughs, or not, caught my eye. The Wall Street Journal discusses a breakthrough in cancer therapy using HIV to target cancer cells. The news is mostly good but the lead researcher worries that it was only luck which prevented the FDA from ending the research prematurely:

Cytokine-release syndrome almost ended the therapy in its infancy. In 2012, Dr. June’s first pediatric patient, 6-year-old Emma Whitehead, developed a 106-degree fever and experienced multiple organ failure. “We thought she was going to die,” he recalls.

A blood analysis showed high levels of the cytokine interleukin-6, or IL-6. “I happened to know because of my daughter’s arthritis that there was a drug that could target IL-6—that had never been used in oncology,” Dr. June recalls. Fortunately, the children’s hospital where Emma was being treated had the medication, Tocilizumab, on hand. “We wouldn’t have had it at the adult hospital because it wasn’t approved at that point for adult conditions.”

Within hours of receiving the drug, Emma awoke from her coma. “It was literally one of those Lazarus conditions,” Dr. June says. Eight days after receiving the CAR T-Cell injection, she went into remission. Two weeks later, she was cancer-free. She’s now 12 and thriving.

Tocilizumab “saved the field” as well as the girl, Dr. June says. “If the first patient dies on a protocol and nobody’s been cured, you’re over.” Regulators, he adds, always “err on the side of caution.” That irks him, since most of his patients would die without the experimental treatments: “Our FDA regulations are made so that you can never have more than about 30% of people get sick with serious side effects. I think we don’t have enough leeway for side effects when you have a potentially curative therapy.”

In my TED talk I argued that the richer China and India are the better it will be for US cancer patients because the bigger the market the greater the incentive to research and develop new drugs. US patients may also get a second benefit. China is big enough to move world R&D which previously was true only for the US and to a lesser extent (because of price controls) the EU. Since the US has by far the largest pharmaceutical market the FDA is a regulatory hegemon. With China we may get to see for the first time a serious alternative to the FDA. And according to some observers, China’s approval process is less-risk averse.

Some of those [new trials] are in the U.S., but more are taking place in China. “There’s a lot more people there, so you can do a lot more trials,” Dr. June says. “But they also put more of their GDP into medical therapy, particularly CAR T-cells.” Beijing’s drug-approval process is easier, too.

I don’t know whether that is true, but it’s a hopeful sign.

In another story, Lawrence Reed has the inspiring story of Bill Halford who has developed a not-yet-approved vaccine for Herpes. Herpes can be incredibly painful and it infects over one million people a year but the route to a vaccine has not been easy:

Impatient with Washington, Halford injected himself, his family and a group of ten herpes patients. None of his family exhibited any ill effects, evidence that the vaccines were safe. All the sufferers enjoyed dramatic pain relief, suggesting effectiveness. The early success of his research led him to co-found, along with film-maker and entrepreneur Agustin Fernandez, a company known as Rational Vaccines, Inc. (RVx)). Its mission is to fight the herpes epidemic worldwide, using the live, attenuated strains that Halford created.

Peter Thiel is a lead investor in Rational Vaccines. Sadly, Bill Halford contracted cancer and died this year at just age 48. I hope his company will carry the ball over the goal line.

Should we all be taking Metformin? Metformin is a diabetes drug but researchers have found that the people taking the drug also get dramatically fewer cancers. Here is Wired:

What they discovered was striking: The metformin-takers tended to be healthier in all sorts of ways. They lived longer and had fewer cardiovascular events, and in at least some studies they were less likely to suffer from dementia and Alzheimer’s. Most surprising of all, they seemed to get cancer far less frequently—as much as 25 to 40 percent less than diabetics taking two other popular medications. When they did get cancer, they tended to outlive diabetics with cancer who were taking other medications.

As Lewis Cantley, the director of the Cancer Center at Weill Cornell Medicine, once put it, “Metformin may have already saved more people from cancer deaths than any drug in history.” Nobel laureate James Watson (of DNA-structure fame), who takes metformin off-label for cancer prevention, once suggested that the drug appeared to be “our only real clue into the business” of fighting the disease.

It’s not just Wired. Here is the title of a recent meta-analysis:

Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis.

Metformin is already approved so it could quickly be used off-label  but there is a big problem with anti-aging drugs–there is currently no way any anti-aging drug can get approved.

The assembled scientists and academics focused on one obstacle above all: the Food and Drug Administration. The agency does not recognize aging as a medical condition, meaning a drug cannot be approved to treat it. And even if the FDA were to acknowledge that aging is a condition worthy of targeting, there would still be the question of how to demonstrate that aging had, in fact, been slowed—a particularly difficult question considering that there are no universally agreed-on markers.

The FDA should provide a path to approve anti-aging drugs but if not maybe the CFDA will.


If metformin reduces "diseases of ageing" then it is possible to demonstrate in trials that it indeed prevents specific conditions. On that basis, it can be approved for those new indications. I suspect the evidence isn't actually very strong, however, like lots of medical mirages.

However, if physicians are confident, they are free to prescribe metformin off label, so there is no FDA barrier. The drug is very cheap, so insurer coverage is not a factor. Again, I suspect this is not happening because the evidence is not there.

You are answering your own question.

> it is possible to demonstrate in trials

> there is no FDA barrier. The drug is very cheap

Sorry for confusion. I am simply saying Alex is doubly wrong. Here:
1) If a company wanted approval, they could get it (assuming it works).
2) Even if not, patients currently have access to this therapy for anti aging uses, assuming their doc buys in to the weak evidence.

Even simpler, if metformin is that good........the black market sales would be as thriving as the opiates one.

Also true.

Opiates give quick pain relief so a strong candidate for the black market if doctors restrict use, while Metformin looks like it reduces the incidence of cancer and heart disease where a good dose isn't clear yet. There are reports that many doctors have started to take Metformin, though.

Would love to see some survey data on that!

I will release survey data in a few weeks and the good news is that only some of it is fabricated but only where smoothing over annoying inconsistencies was necessary.

Andrew, Andrew Wakefield? I'm such a huge fan, what an honor.

10 cents per 1000mg metformin tablet. That explains the absence of black market

The drug is cheap, is the FDA really blocking the advancement of health care here?

Um, black market sales thrive exclusively for pharmaceuticals with very tight feedback loops - like opioids, benzodiazepines, etc. Drugs like metformin, rapamycin-analogues etc. may have large effects on mortality and the development of age-related diseases, but you wouldn't be able to experience those effects on an individual level in any noticeable time frame.

" if metformin is that good……..the black market sales would be as thriving as the opiates one"
The metformin doesn't seem to get me high like the opiates do, man.
But seriously, the pain relief from opiates is immediate, but these supposed benefits from metformin are not going to be as obvious to the user, so, even the black market needs data in order to drive it.

"... because the evidence is not there.."

Yes, by now we should all be highly skeptical of dramatic 'medical breakthroughs' ... which seem to come frequently in mainstream news. Despite the hi-tech aura, most medical research is low quality and of questionable objective value. Scientific research in general suffers the same problem.

Most medical doctors are not interested (nor trained) in statistical probability theory or decision trees, despite the fact this is the underlying core of everything they do. It's very important in evaluating not only the results of the many medical tests/treatments in use (or possible)-- but whether the test/treatment itself is of any value at all in the first place. Evaluating the efficacy of a specific drug on the 'general population' is quite difficult.

Of course doctors could focus on easier, more productive things-- like not killing patients via preventable medical errors (...the 3rd leading cause of deaths in U.S.)

Yes of course, it's certainly not productive to cure cancer, good point

By the way that "study" on medical errors is garbage and off by a factor of ten. Read Scott Alexander on it for example

There seem to be a lot of people already taking Metformin at different dose levels. It should be possible to data mine their health records.

That is exactly what is already done in a number of the cited studies, but that can't prove causality and if it could, it can't prove benefits in healthy people rather than sick people (because healthy people do not currently take metformin and show up in health records).

Pascal's wager?

$5 a month is pretty cheap considering no side effects and the potential to dramatically decrease mortality in the aggregate.

What Len says above, "medical doctors are not interested (nor trained) in statistical probability theory or decision trees, despite the fact this is the underlying core of everything they do", is the most important point in this discussion.

Weak evidence is not precisely the same thing as no evidence. Again, Pascal's wager.

It's not Pascal's wager because there are no infinities. Metformin is not as good a buy as it looks because you have to do with the possibility of nasty GI problems, and the reduction in mortality risk buys you fewer days of life than you would expect before you run the numbers, so the $5 a month is buying you not that much, and then you have to discount the benefits because you start taking metformin in your 30s or 40s and the gains would take many years to show up.

In any case, if you were doing this cost-benefit analysis, you would start with a meta-analysis of the diabetes RCTs, whose causal conclusion only *might* be nontransferable to healthy people, rather than health records which you *know* are not accurate causally for anyone much less you.

Hi Jan,
The studies included in the systematic review are observational which opens the findings up to potential bias. However some of the findings you would expect to be biased in the opposite direction (such as diabetics on metformin having lower mortality than non-diabetics) so this abrogates the risk of a "mirage" somewhat. Even so the author (me! hello :) does recommend that clinical trials are needed before any one starts taking metformin for aging.

In Elite Health Care Experts News, a fraud was exposed-

Read down to second article and be shocked.

I have a few questions about drugs and FDA approval.

(1) If the FDA does not recognize aging as a medical condition, then why do anti-aging drugs need FDA approval to be sold, i.e., what defines a "drug"? Why would an anti-aging product, a product administered by ingestion or needle but not necessarily called a "drug" intended to achieve (what the FDA considers) a non-medical purpose, require FDA approval (or even a prescription)? For example soda, which is intended to treat the non-medical condition of wanting to drink something that tastes good, does not need FDA approval.

(2) Do clinical trial results and drug approval in China (or any other foreign country) help speed FDA approval for sale in the US? If not, then how will looser CFDA standards help US patients? If yes, then why don't US drug companies already run foreign trials in loosely regulated countries (China, India, Africa?), even if those countries are too poor to pay high drug prices, just to gain quicker approval in the US? When Alex says a richer China and India will be better for the US because the fixed costs of R&D can be spread over a larger market, I agree. I also agree that a more loosely regulated country can benefit the US by providing an alternative path to approval, provided that approval in that foreign country can somehow speed approval in the US. However, it seems like the loosely regulated countries shouldn't need to be the same ones as the rich or growing richer countries because drug companies presumably can cross-subsidize internally?

(3) If a drug has not yet been approved for sale to patients by the FDA, is there a way the drug can be "shared" with patients over an Uber-for-drugs sharing network?

I guess what I'm really asking is, other than off-label use, why are there not more efforts to find "loopholes" to work around burdensome FDA approval? We seem to be quite innovative in reducing taxes but not so innovative in reducing time-to-market in the face of regulation. Is one explanation that incumbents actually like burdensome regulation as a way to keep out competitors? If so, then might we expect drug companies to inhibit FDA deregulation, at least in the case of deregulation that would reduce fixed costs, which tend to be barriers to smaller upstarts?

(4) One more question, does the CBO score how many people "lose" their medication as a result of long FDA approval processes? If not, why not? The CBO may be non-partisan, but the choice of *what* to score in terms of how many people "lose" something seems to reflect some sort of pro-regulation bias. Regulation tends to reduce supply, but I've never heard of regulation being scored on how many people will "lose" or "lose access to" the product in question until recently with health insurance. The terms "lose" and "lose access to" would seem to apply much more to regulation that prohibits purchase than to de-regulation that no longer mandates purchase.

By the way, since the Oregon Medicaid expansion trial failed to prove that Medicaid expansion was effective in improving medical outcomes, shouldn't the FDA withdraw the Medicaid expansion to protect recipients from ineffective treatments?

1) I don’t believe “aging “is a recognized condition. It’s a bit nonsensical as an umbrella term, for various reasons. However, if it works for the specific indications (prevents cancers) that Alex notes above, those can be demonstrated to be prevented. Part of what determines whether something is overseen by FDA is how it is marketed (e.g. Are you claiming that this can prevent or treat a specific condition?) There is also it in between category called dietary supplements, which don’t have to actually do anything, but companies are limited to making much more general high-level claims in their marketing. Obviously manufacturers can fetch much higher prices for actual drugs that are demonstrated to work and approved by FDA.

There are times here where you can imagine the human body is a fine piece of clockwork, and we can know and understand each mechanism. It was a miracle of rare device.

Then you wake up, and could I revive within me that symphony and song.

1) I don't believe "aging "is a recognized condition. It's a bit nonsensical as an umbrella term, for various reasons. However, if it works for the specific indications (prevents cancers) that Alex notes above, those can be demonstrated to be prevented. Part of what determines whether something is overseen by FDA is how it is marketed (e.g. Are you claiming that this can prevent or treat a specific condition?) There is also it in between category called dietary supplements, which don't have to actually do anything, but companies are limited to making much more general high-level claims in their marketing. Obviously manufacturers can fetch much higher prices for actual drugs that are demonstrated to work and approved by FDA.

Meant to reply to BC above.

The FDA did approve an anti-aging trial for Metformin in 2015 and has been considering aging as a disease.

David Sinclair of resveratrol fame is now conducting trials for NMN at a hospital in Boston: "For the past four years, Professor Sinclair and Dr Wu have been working on making NMN into a drug substance with their companies MetroBiotech NSW and MetroBiotech International."

NMN is very similar to NR and both are currently on the market as supplements. I don't know what Sinclair can do to a vitatim B3 derivative to turn it into a drug apart from gaining FDA approval two or three years from now. ChromaDex, a maker of NR, is also trying to get FDA approval for NR to help treat Cockayne syndrome where children age many times faster than normal.


Got a link to the trial or any FDA statements on this? Would be interested to know how they describe "aging" as a disease.

Here is a slide presentation in April 2016 before getting approval:


1) TAME is the result of an 18 month process to develop an approach that provides a pathway for the FDA approval of drugs targeting aging.

2) TAME is feasible and smaller than many previous prevention trials.

3) It has the potential to link biomarkers and intermediate outcomes with a hard clinical endpoint paving the way for biomarker use in registration trials of future compounds.

Interesting. So if my scan of this is correct, they are defining the aging endpoint as a composite outcome made up of a bunch of discrete conditions for which drugs can currently be separately approved. Composite outcomes are tough, especially the more components you add, but if they can make it work, that'd be a huge development.

A couple of thoughts from an industry guy.

First, with respect to the FDA approval question: The Food, Drugs, and Cosmetics Act requires any drug marketed in the U.S. as a "treatment or prevention for a disease or condition" to be approved by the FDA before it can be marketed. This language has some interesting ramifications. For example, you can't get a drug approved for "more and better orgasms". The wording of the law requires that you be addressing a deficit, so we end up with the industry more or less inventing disorders like "female hyposexual response disorder". They catch hell for that, but its mostly a strategy for dealing the wording of the FD&C Act.

"Aging" could probably be a disease or condition, but demonstrating efficacy against such a broadly defined endpoint would be really difficult. Your clinical trial endpoint would probably have to be something along the lines of life extension, and that trial would take a decade or so to run.

In general, its really hard to develop drugs that will do more good than harm in healthy people. If they have a bacterial infection and are going to die, you can give them a drug that kills bacteria, and if they have side effects, well, its still better than death. But the body is a complicated thing and everyone is a little different, so putting millions of mostly healthy people on chronic drug you usually find that the side effects outweigh the benefits. There are only a few exceptions to this so far, mostly in people at high risk of a heart attack.

Generally I think the FDA does a reasonable job. About equal numbers of people criticize it for being too strict or too lax. About 15% of FDA approved drugs eventually are withdrawn as real life experience in large numbers of patients show they cause more harm than good. This suggests to me that they are taking about the right amount of risk.

"This suggests to me that they {FDA} are taking about the right amount of risk."

?? FDA bureaucrats are not the people taking the "risk" of their FDA life & death decisions

" About equal numbers of people criticize it for being too strict or too lax."

So the scientific process, if, indeed, that's what medical research is all about, is validated by some kind of democratic procedure?

Of course, you use science to evaluate drugs according to a regulatory framework, but there's no science behind the framework itself. If people wanted maximum freedom, they'd lobby for less regulation. If they wanted the safest drug supply, they'd lobby for more restrictive licensing. There's no scientific way to evaluate either goal, it's a matter of human preferences.

There is a way to simultaneously please both types of people--remove the prohibition on the marketing and sale of non-FDA approved treatments. Those who think the FDA makes treatments safer can choose to only use FDA approved treatments. Those who disagree won't be forced by Federal police powers into the belief system of the former.

I find it amusing Alex says on one hand the FDA won't recognize aging as a 'condition' and then in another breath says there is no way to measure it. So for someone who tries to be rational and skeptical I'm being asked to rally around a cure for something but there's no way to measure the cure working? Hmmmmm

In reality there's a lot of things that can easily be measured with aging. Whenever a skeleton is found, for example, medical examiners do not have a difficult time determining the age the person died. Metabolism, muscles , skin, organs, cognition, all have objective measures of aging. On top of that you have a huge number of secondary conditions that show up as a result of aging (cardiovascular problems, diabetes, cancer, etc.). There are already a lot of drugs that approved on the theory that by lowering some secondary measure, you're helping a primary measure. For example, lowering BP is thought to prevent heart attacks and strokes. Hence there are drugs approved based on the demonstration that they lower BP but whether that ultimately results in fewer heart attacks or strokes remains as a question that needs more data and studies to know for sure.

I do think we have to think about the problem of discovery when we end up with more and more generic drugs as time goes by. Will the next great breakthrough be in a new drug? if so there's powerful incentives for that R&D to be carried out. Or will it be a new use for an old drug or combination of old drugs? How is that made into an incentive? I don't have an easy answer for it but we should think about it.

The FDA will approve drugs based on so-called "biomarkers", which are measurements of structural or functional changes thought to be predictive of outcomes of actual benefit, but increasingly demands a large body of data demonstrating that the biomarker used is valid. For example, many drugs have been approved to prevent heart attack based on their effect on total, low density-, or high-density cholesterol, some of which failed to actually prevent heart attacks in larger trials conducted post-approval. On the other hand, diabetes drugs are still approved based on their ability to lower blood sugar based on the Agency's belief that blood sugar is a reliable biomarker for prevention of diabetic complications such as blindness.

For aging I can't really think of anything that is widely accepted as a reliable biomarker predictive of longevity.

One physical marker of aging is diminished strength. A couple of manufacturers of synthetic human growth hormone tried to look at improved muscle strength in an elderly cohort of patients. Nothing came of the studies.

Below is a useful discussion of the landscape for repurposing old drugs. I agree financial incentives are an issue, but those dynamics make this a good area for government-supported research that could yield affordable therapies.

Actually, there is a way to measure it. There are off-the-shelf instruments for measuring endothelial function, which is highly correlated with age and health risk. They work by injecting a drug that causes vasoconstriction and measuring the response. If your blood vessels are unresponsive, that's bad.

Right now, measuring endothelial function requires an invasive procedure (injecting a drug and in some methods inserting a subcutaneous sensor for blood flow). But there is a possibility that a sensor can be developed which can be built into something like the Apple Watch or FitBit fitness band. This would be a high-resolution sensor for blood flow which would measure the dicrotic notch. Your pulse has a double hump, and the valley between the two humps is the dicrotic notch. The deeper it is, the better. In old people, smokers, obese people, and sedentary people the notch diminishes and may even disappear.

The hope is that someday your watch or fitness band will be able to alert you in a timely way to bad behaviors which adversely affect your health. If you smoke a cigarette or drink a sugary soda, within 5 minutes your watch will start flashing red warning signs. That might change your behavior.

Yes. I guess the point I was trying to make is that the FDA standards for biomarker based claims are fairly high. There is a whole FDA website on the subject here.

Part of what makes it complicated is that observational correlations don't always predict the effect of pharmacological manipulation. For example, high HDL is associated with reduced CV risk in observational studies. But drugs that raise HDL don't decrease CV risk.

>>The hope is that someday your watch or fitness band will be able to alert you in a timely way to bad behaviors which adversely affect your health.<<

There, along with India and China, lies the answer to taking back important aspects of individual freedom from the FDA.

If an app popular outside the US significantly reduces or controls a severe medical condition, it'll be interesting to watch the control freak contortions of The Regulators before they throw in the towel. Congress may even pass meaningful reform - tossing "Safe And Effective" into the trash can of history.

If all you're doing is alerting people when they smoke a cigarette or drink a sugary soda, I don't think FDA has that in their purview. If you were diagnosing disease, that would be a whole different kettle of fish. Measuring blood sugar for the purpose of treating diabetes would be heavily regulated and rightly so. But I have a fingertip pulse oximeter which very nicely displays my pulse waveform (and I've got a very good dicrotic notch for someone of my age), but nobody is using these things to diagnose disease. If that's not happening, FDA doesn't care. But if it's a blood glucose meter or a blood pressure meter, the FDA very much cares as well they should.

These things can be marketed now, without FDA oversight. Nobody has a problem with that. Only issue is that they aren't really that effective in helping people stay healthy.

If you're talking about a fingertip pulse oximieter, yeah they don't give you any useful or actionable data. But if you're talking about a future wearable device which can rapidly report endothelial dysfunction, that hasn't happened yet. That could be revolutionary. It would give you immediate feedback on your bad behaviors. And it would be objective because it's measuring physiological parameters -- it doesn't know you just smoked a cigarette, all it knows is your stats crashed 5 minutes ago. Whatever you're doing, stop doing it.

"If you smoke a cigarette or drink a sugary soda, within 5 minutes your watch will start flashing red warning signs. That might change your behavior"

Wow, behold the power of wearable tech! [why does one need an Apple Watch to know these behaviours are bad for you?]

That's not a compelling Use Case.

Will 500,000 Americans a year die -- for lack of $30 million?

Fatalities from accidents and homicides in the US every year are a far distant second and third to the half a million Americans (and uncounted millions around the world) who die from heart failure. There now there looks to be a stabilizing procedure for most all and an actual cure for many … but from Sunshine Heart, C-pulse device e-news I get, being $20-30 million short to fund final clinical trials stands between those millions and the rest of their lives.

It goes like this. A trial with 20 very ill patients (stage III, stage IV HF, with at least one hospitalization and considered for another device) ended in 2012 with 5 complete cures (device removed), the majority improved and none worse.

Novel, implantable device 'could slow, reverse heart failure', Honor Whiteman, Tuesday 7 October 2014
”Around 50% of people who develop heart failure [5.2 million Americans] die within 5 years of diagnosis. But could a novel, implantable heart device change this? In a clinical trial, the C-Pulse - a cuff that wraps around the aorta and pumps blood from the heart around the body - has proved effective in reversing heart failure, even in some patients with severe cases.”

No problems with clots or strokes with the C-pulse balloon outside the bloodstream. Implanted non-invasively too.

Sunshine Heart has been working up a final trial with 200 patients to win FDA approval but can’t seem to get past 100. Money seems the bigger obstacle.

“Unfortunately, there don't appear to be easy solutions to Sunshine Heart's primary problem - it lacks the resources of major cardiology companies like Boston Scientific (BSX), Medtronic (MDT), or St. Jude Medical (STJ) that could otherwise support and encourage enrollment. Getting the FDA's permission to run an interim analysis would certainly help, and the shares do appear undervalued, but the company is...”

One email from Sunshine Heart (can’t dig it out) made out private investors to be reluctant for fear any patent could be too easily worked around.

Here’s the thing. I figure 5 million currently terminal patients (we all know somebody) would gladly pony up $6 apiece. :-) More sensible path – government supporting this and all clinical trials from now on – possibly neutralizing big pharma’s biggest gouging excuse without hampering innovation (encouraging) – in this case, with 10,000 American deaths every week, pronto. Maybe states could get together and pitch in. Maybe GoFundMe. ??? Whatever, soon.

HF is a huge market and $30M is a pittance by the standards of medical product development costs. I'd think they'd have no trouble at all raising this amount if people thought this was going to work.

They've had problems with infections of the external drive line and with enrolling their clinical trial. If you can't enroll people for the trial, that's usually taken as a sign that the market for the product is very small. People don't want their chests cracked open for an experimental device because the existing data suggests that it is only going to work as a bridge to transplant, and there are already devices available for that.

This part is out-dated:

"Around 50% of people who develop heart failure [5.2 million Americans] die within 5 years of diagnosis."

That statistic is still often used but is based on a study that looked at heart failure patient outcomes from the 1970s and 1980s. Quite a bit has changed in the past 25 years with better treatments coming in the next few years.

The answer to your question is, simple enough: No.

The answer is found in jellyfish,


Was it catfish?

"FTC, New York State Charge the Marketers of Prevagen With Making Deceptive Memory, Cognitive Improvement Claims"


Agree with Jan's analysis above.

Victimization takes many forms and has many wrongdoers. We know that victimization is the motivation for many followers of the alt-right. Having come of age during the Great Recession, they believe they are victims of racists, black racists, a black man having been president as many in the white working class suffered economic calamity. That the black president would be blamed for a financial and economic collapse he inherited is but a symptom of victimization, a victimization promoted by the white elites whose policies led to the collapse. It's an impressive political trick: the white elites whose polices contributed to the collapse being sold to the white working class as their last line of defense against the forces of darkness led by the black president. Even more impressive is the spectacle of billionaires joining the white working class as sufferers of victimization. We see it in snake oil salesmen suffering victimization at the hands of the FDA for withholding approval of their snake oil. We see it in rapacious bankers suffering victimization at the hands of the SEC and Treasury for trying to reign in the their conduct that led to the financial crisis. Of course, snake oil salesmen and rapacious bankers would like to castrate the government agencies that would restrict their ability to sell snake oil and be rapacious. To his credit, Cowen's blog posts have been emphasizing the distinction between perception and reality. I assume he prefers reality, provided reality doesn't conflict with his ideology. Am I being cynical, or simply acknowledging reality.

Yes, anyone against more government regulation is clearly either a racist, a fascist, a rapacious banker, or a billionaire snake oil salesman. We need some new government regulations to protect ourselves against these people who refuse to acknowledge that more government is always better government and that the common people can't be trusted to properly defend themselves against racists, fascists, rapacious bankers, and billionaire snake oil salesman. As Jefferson said "The government that governs most is the government that governs best".

Folk medicine: it's from goat's rue.

Link does not work, but Metformin does.

The post and many of the comments, especially re metformin, demonstrate considerable confusion about the state of things. Here's the clinical trials link to the first of its kind FDA approved ongoing metformin study: Note the condition being treated - "Aging"

The claim that if anti-aging treatments were effective everybody would be taking them assumes that everybody knows about them and are willing to religiously take pills that never produce any noticeable effect in their lives. Rapamycin, metformin and the pro-autophagy and mitochondrial nutrient supplements today are like seat belts 50 years ago. Most thought of them as a nuisance and only useful in situations they would rather not think about. Over time it emerged that the early adopters were, on average, dying less often on the roads than others and usage steadily climbed.

I assure you there are plenty of early adopters out there when it comes to drugs affecting metabolism signaling, cell waste recycling and mitochondrial function. All of the doctors and most of the lawyers I know are already on one or more of them. But you have to be willing to think "these won't turn back the clock or make me handsome or give me a 4 hour erection but i might be one of the lucky takers in whom e.g. pancreatic cancer is suppressed, and I'll never know it and go to my grave at 85 wondering if all those damned pills did any good."

Here's something new:

Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis.
Review article
Campbell JM, et al. Ageing Res Rev. 2017.

This systematic review investigated whether the insulin sensitiser metformin has a geroprotective effect in humans. Pubmed and Embase were searched along with databases of unpublished studies. Eligible research investigated the effect of metformin on all-cause mortality or diseases of ageing relative to non-diabetic populations or diabetics receiving other therapies with adjustment for disease control achieved. Overall, 260 full-texts were reviewed and 53 met the inclusion criteria. Diabetics taking metformin had significantly lower all-cause mortality than non-diabetics (hazard ratio (HR)=0.93, 95%CI 0.88-0.99), as did diabetics taking metformin compared to diabetics receiving non-metformin therapies (HR=0.72, 95%CI 0.65-0.80), insulin (HR=0.68, 95%CI 0.63-0.75) or sulphonylurea (HR=0.80, 95%CI 0.66-0.97). Metformin users also had reduced cancer compared to non-diabetics (rate ratio=0.94, 95%CI 0.92-0.97) and cardiovascular disease (CVD) compared to diabetics receiving non-metformin therapies (HR=0.76, 95%CI 0.66-0.87) or insulin (HR=0.78, 95%CI 0.73-0.83). Differences in baseline characteristics were observed which had the potential to bias findings, although statistical adjustments were made. The apparent reductions in all-cause mortality and diseases of ageing associated with metformin use suggest that metformin could be extending life and healthspans by acting as a geroprotective agent.
Copyright © 2017. Published by Elsevier B.V.

Did you even read the post? Tabarrok cites and links to that meta review.

Yes but stupidly copied the wrong abstract in my haste. Meant to riff on the pancreatic cancer thing. At least I didn't copy and paste pr0n like that ESPN announcer awhile back. Here's what I intended:

Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer
Ke Chen, Weikun Qian, [...], and Qingyong

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 7%. Accumulating evidence has revealed the cancer preventive and therapeutic effects of metformin, one of the most widely prescribed medications for type 2 diabetes mellitus. However, its role in pancreatic cancer is not fully elucidated. Herein, we aimed to further study the preventive and therapeutic effects of metformin in genetically engineered mouse models of pancreatic cancer.

LSL-KrasG12D/+; Pdx1-Cre (KC) mouse model was established to investigate the effect of metformin in pancreatic tumorigenesis suppression; LSL-KrasG12D/+; Trp53fl/+; Pdx1-Cre (KPC) mouse model was used to evaluate the therapeutic efficiency of metformin in PDAC. Chronic pancreatitis was induced in KC mice by peritoneal injection of cerulein.

Following metformin treatment, pancreatic acinar-to-ductal metaplasia (ADM) and mouse pancreatic intraepithelial neoplasia (mPanIN) were decreased in KC mice. Chronic pancreatitis induced a stroma-rich and duct-like structure and increased the formation of ADM and mPanIN lesions, in line with an increased cytokeratin 19 (CK19)-stained area. Metformin treatment diminished chronic pancreatitis-mediated ADM and mPanIN formation. In addition, it alleviated the percent area of Masson’s trichrome staining, and decreased the number of Ki67-positive cells. In KPC mice, metformin inhibited tumor growth and the incidence of abdominal invasion. More importantly, it prolonged the overall survival.

Metformin inhibited pancreatic cancer initiation, suppressed chronic pancreatitis-induced tumorigenesis, and showed promising therapeutic effect in PDAC.

Good for mice not getting mouse intraepithelial cancer in KC mice.

That paper is really a crappy meta analysis, if you can even call it that.

A traditional meta analysis looks at all the trials that have randomized patients to treatment A or Treatment B (which may be a placebo). You then compile the results across the trials. It works in part because the trials are all randomized, and in principle the only difference between the arms is the treatment.

What these guys did was take the death rate of people treated with metformin in diabetes trials and compare them to people with other diseases who were treated with placebo. God only knows what diseases these people had. It certainly isn't a comparison of identical populations w/ or w/o metformin.

The paper tells us nothing and should not have been published.

I agree. I pasted the wrong thing. Meta analyses of non-preregistered studies using QRPs are at best a waste of time.

It compares diabetics with and without metformin

Agreed. Which means that it does not compare non-diabetics with and without metformin.

yes. There is a long history of debate on that issue. Most diabetics die of heart disease, and some early studies found that patients treated with metformin are less likely to have a heart attack than those treated with certain other antidiabetic drugs. But in that case it is hard to tell whether metformin is reducing heart disease or the alternative drugs are increasing it. There is some indirect evidence that it is the latter.

Metaformin is also a bodybuilding drug, like steroids and HGH. Lose weight without losing muscle, get that paper thin skin look.

These amazing, astounding fix everything drugs come along from time to time. There are all kinds of things that well meaning people have touted and swallowed. I remember when Jack Dreyfus, an early stock fund manager and therefore seriously rich guy, was promoting Dilantin in the early 1970s. I have read about mineral water, radium water, and water from special springs as being great. Let's take all this with a tiny bit of caution. Mouse data is always interesting, but lab mice are genetic anomalies that can be bred to prove just about anything. I bet that a lab mouse strain that dies instantly when exposed to a few molecules of metformin is commercially available.

The mice are not "bred to prove anything" and in the case of Metformin there is already the human evidence that something positive is likely happening. The anti - aging field wasn't around in the 1970s and tiny until 2003 or so. There were four labs researching this area in the 1990s and now over 400. Worlds apart.

"The anti-aging field wasn't around in the 1070's..." or earlier.

Ever heard of Ponce de Leon who searched for the fountain of youth?

Junk science has been around for a long time.

All people are saying is apply scientific principals, and recognize that those who don't make money on those who do not.

"principles". I am often without them so I don't recognize them when I see them.

"Ever heard of Ponce de Leon who searched for the fountain of youth?"

Of course! Ponce would have been my beer buddy had I lived in the early 1500s. From what I've read, he was so close to developing CRISPR but sadly died just 500 years too early to see his idea come to fruition.

"Impatient with Washington, Halford injected himself, his family and a group of ten herpes patients. ... Sadly, Bill Halford contracted cancer and died this year at just age 48."

I sure hope those two sentences are not causally connected.

I am someone who has been taking Metformin for 16 years as a treatment for my P.C.O.S. and Insulin Resistance. I have a crazy high inflammation factor due to eating too many processed foods off and on over that 16 year period. My doctor recently made me have all sorts of scans to test for clogged arteries due to those high numbers of LDL.......she was SHOCKED to find out that as overweight as I am from eating a Food Pyramid Diet and taking Metformin with Thyroid meds, I have NO PLAQUE on my arteries even though my Inflammation markers say I should have some. In fact since changing my eating lifestyle to a ketogenic one, by eating no processed foods, no refined carbohydrates, and taking metformin and thyroid meds, I have dropped 20 lbs in 30 days, by eating and intermittent fasting....Metformin has kept my insulin down through a controlled blood sugar A1c value of no more than 5.5 for the last 16 years.....I honestly think that if you control blood sugar and insulin, stop eating processed foods, get rid of processed carbs and sugar, and increase your non processed SATURATED FAT intake by 10 fold, while reducing protein and carbs, you know like our Great Grandparents in the 1940s did, you will not only prevent cancer, diabetes, but Alzheimers and Epilepsy....or at least control them better......I have only one problem with Metformin and it gives me and most folks tummy troubles. I always have to be by a restroom, BUT I have recently cut my dosage down by 1/2 and have less of a problem.....I must be a living example of how metformin is used to help folks not yet diabetic, prevent heart disease.....

Is it true that taking metformin means giving up alcohol? I've heard drinking while on metformin can be fatal.

The FDA's role should be strictly informational. It should not have any power to proscribe any behavior. Just make risk assessments public and let the people who face the risks make their own choices.


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