Background on Four Types of Stem Cell Research

This blog post contains general background information on four types of stem cell research.  I'm writing it because the term "stem cells" is used to describe several different lines of research, and it is important not to mix them up.  Good news from one type of "stem cell" research should never be used to suggest that a different type of "stem cell" research is going to be successful.

Quick Summary
Here is a very quick summary of four types of stem cell research:
1. "Burt"  Reboots the body's immune system to stop the autoimmune attack.  First, the patient is given very powerful drugs to shut down their immune system, then they are given drugs which causes the body to mobilize it's own adult stem cells to rebuild the immune system, without the autoimmune flaw.  Has resulted in the best cure results of any research to date, but is also the most dangerous.
2. "Zhao"  Patient's immune cells are removed and stem cells from the umbilical cord used to help retrain them   to stop the autoimmune attack.  The immune cells (without the stem cells) are then put back in the patient.  Good results and appears to be much safer than Burt.
3. Several companies (example: Viacycte) are attempting to grow new beta cells from stem cells.  They are taking undifferentiated stem cells and trying to find the recipe to cause those stem cells to differentiate into beta cells.  None of this work is in human trials right now.
4. Many stem cell clinics (example: Xcell) will infuse bone marrow stem cells in the hopes that this will cause the patient to regrow beta cells and improve their type-1 diabetes.  Although many clinics will provide this service, I have never seen a peer reviewed study showing that it improves type-1 diabetes.

How They Are Different

Burt
Burt's research does not use external stem cells.   Rather, the patient is given a drug which "mobilizes" their own internal stem cells.  People have several different forms of adult stem cells in their body.  Part of Burt's protocol is to give the patient a drug which is well known to cause them to generate more of their own bone marrow stem cells, and cause these cells to be released into the blood stream.

Zhao
Zhao's research is very different from the rest, because he is not trying to grow beta cells from the stem cells.  Instead, he is using them to train the immune cells not to attack beta cells.  (This is sometimes called "curing autoimmunity".)

You may ask, "why should stem cells cure autoimmunity?"  It's a very good question, and I don't know the answer.  But I'm not an immunologist, and for me it is far more important that a treatment work, than that I understand how it works.  Many treatments are used for years before we understand exactly why they work.  (Aspirin is a 100+ year old example.)

Beta Cells from Stem Cells
There are several companies working on ways to differentiate beta cells from stem cells.  Generally, they differ from each other two ways.  First, in the kinds of stem cells they start with (embryonic from an embryo, embryonic from cord blood, or different types of adult cells or adult stem cells that have been treated in some way to make them undifferentiated).  Second, in the recipe they use to transform these undifferentiated stem cells into beta cells.

Stem Cell Clinics
These guys harvest bone marrow stem cells from a person, and then put them back into that person or a different person.  They differ in exactly how they put the stem cells back in (in the blood or directly in the organ that needs them), and also in what processing or separation is done to the bone marrow cells before being put back.

My opinion of the stem cell clinics is very low.  They are a cash up front business without evidence that they help anyone.  For example, to approve a new drug, the US FDA requires four clinical studies to show that it works and is safe.  Currently, there is not one stem cell clinic, that has published even one peer reviewed study (that I have found), that shows that it works.

Most of these clinics are in third world countries, but there was one, called Xcell in Germany.  Years ago, Xcell said that they were running two studies to show that their treatment would help type-1 and type-2 diabetics, respectively.  Neither of these studies were ever published in a peer reviewed journal, and last year the German government shut down Xcell after an 18 month old baby died of complications from a stem cell treatment at the clinic.  (And this after a 10 year old boy almost died after the same procedure!)

I often see these clinics cite Burt's work as peer-reviewed, scientific research that suggests their clinics are on the right track. But this work is wildly different from the work done at these clinics and the success of one does not support the treatment of the other.  As an example: Burt uses three drugs in his trial.  These clinics sometimes use one of those drugs, and sometimes none at all.  They never use all three of them, and never get close to the same procedures that Burt uses.  My guess is that you will see these guys citing Zhao's work soon as well, even though Zhao is using a totally different type of stem cells and not even putting in the patient.


Other Terms to Understand

Adult vs. Embryonic
These are the two types of stem cells that we have heard about for the longest, and the loudest.  Much of the arguments about stem cells (especially in the US) are phrased in terms of Adult vs. Embryonic.  However, I have come to believe that, while this difference is critical religiously, politically, and socially, that it is not important in terms of research aimed at curing type-1 diabetes.

The confusion comes from the fact that in the early days of stem cell research, embryonic stem cells were the only undifferentiated stem cells known.  So when people talked about the power of embryonic stem cells, they were often talking about the power of undifferentiated cells.  However, now we can get several different types of undifferentiated stem cells from adult sources, and from different embryonic sources.

Differentiated vs. Undifferentiated
A better way to talk about stem cells, is undifferentiated (and if so, what is their source) vs. differentiated (and if so, how were they differentiated). Differentiated stem cells are those which have already specialized into a specific type of cell. For example, a beta cell. Undifferentiated stem cells have the potential to do this, but have not yet done it. With the current research results, it appears that undifferentiated are not useful for growing beta cells in the simple minded way used by the current clinics. However, both Burt and Zhao have had success using them in other ways, and undifferentiated stem cells have not yet been tested (in people) as a source for growing beta cells.
A lot of the recent news in stem cell research is reporting on different ways to create different types of undifferentiated adult stem cells.  These different type stem cells might have different properties and be good or bad at different things, but we really don't know yet.

Another type of research news that we have gotten recently, but is not as common, is success in turning different types of undifferentiated stem cells into beta cells.  It is especially important to turn them into beta cells that generate insulin when presented with sugars.  The has been some success at this, but none of it has progressed into human trials (that I know of) as yet.  Even if they did, we would still need to either encapsulate them or cure the autoimmunity before they would be a cure for type-1.

Self vs. Others
Any kind of stem cells can be gotten from the person being treated (self) or from someone else (others).  This is true for both embryonic stem cells, and adult stem cells.   You can get embryonic stem cells (for example, from the cord blood) and use them on the person you got them from.  Or you can get adult stem cells from that same person.   Self stem cells are going to have fewer immune issues than those from others.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Possible Cures for Type-1 in the News (January-2012).

Osiris's Prochymal fails in a Phase-2 Clinical Trial
For background, please read my previous blogging on Osiris: http://cureresearch4type1diabetes.blogspot.com/search/label/Osiris

The PROCHYMAL treatment has been shown safe in several phase-I, II, and even III trials for several immune diseases, so they are trying it with type-1 diabetes. This is an adult (actually self) stem cell treatment. Since safety is established, they went straight to phase-II clinical trials. The company's description is this: "Prochymal is a preparation of mesenchymal stem cells specially formulated for intravenous infusion. The stem cells are obtained from the bone marrow of healthy adult donors."

The results were a total failure: no change in the primary end point (C-peptide after a meal), or in any of the secondary end points.   No safety issues turned up.  This was after 1 year, and they will continue to follow the patients for another year.


News coverage: http://www.thestreet.com/story/11362832/1/osiris-stem-cell-therapy-fails-diabetes-trial.html
BTW: most news coverage of type-1 research is superficial.  They just repackage the press release, occasionally adding a quote or two from the company; sometimes not even that much.  But this article in "The Street" is much better than that, and is fun to read.

Background on mesenchymal stem cells:  http://en.wikipedia.org/wiki/Mesenchymal

Should We Give Up On Adult Stem Cells?

The short answer is "no".  But the full answer is a lot more interesting, but will need to wait for another blog posting.  The short version of my opinion is this: based on all the studies done so far, including this one, I don't think that just dumping a bunch of bone marrow stem cells into the body is likely to cure type-1 diabetes.  But that does not apply to stem cells specifically tailored for insulin production, because they are quite different, and so far we have no experience with them in people.  Remember that there are many different types of stem cells, and many different ways of differentiating stem cells, and many different uses of stem cells.  So while there is considerable bad news for the simple minded idea of dumping in a bunch of bone marrow stem cells and expecting a cure, there are many other avenues still open.   That is why I think I will need a whole blog entry to sort out possible stem cell cures.

Dr. Taback et al in Winnipeg Hope for Funding for Vitamin D Prevention Study

As part of my recent policy change to cover treatments designed to prevent type-1 diabetes, I'm starting to cover this potential clinical trial of Vitamin D.  I previously blogged once on Vitamin D, here:
http://cureresearch4type1diabetes.blogspot.com/2010/08/cinnamon-and-vitamin-d.html

Dr. Taback has put in the paperwork to ask for funding for a large, prospective study to see if giving people Vitamin D will lower the rate of type-1 diabetes.  The basic plan is to screen 60,000 babies to find about 5,000 at higher risk for type-1, and then give those babies about 2000 IU of Vitamin D per day (current suggested dose is 400 IU). And then follow them for years to see if fewer develop type-1.

Although no mechanism is known, a few studies [r3] have had promising results, so it makes a lot of sense to test this in a larger group.  Previous promising studies are summarized in [r1,r2].

An older study [r4] showed that Vitamin D consumption during pregnancy was NOT associated with  markers for type-1 diabetes.  Although this [r5] study just published recently suggests that it is associated with type-1 diabetes.  The newer study was of much higher quality than the older one for two reasons.  First, it measured actual cases of type-1, not markers.  Second, it measured actual Vitamin D levels in the person, while the older study had people fill out a questionnaire about diet (which is vastly less accurate).

News coverage: http://www.cbc.ca/news/health/story/2011/12/28/diabetes-type1-vitamin-d-chasing-cures.html

[r1] http://www.ncbi.nlm.nih.gov/pubmed/18339654
[r2] http://www.ncbi.nlm.nih.gov/pubmed/15671235
[r3] http://www.ncbi.nlm.nih.gov/pubmed/11705562
[r4] http://www.ncbi.nlm.nih.gov/pubmed/20369220 
[r5] News: http://www.foodconsumer.org/newsite/Nutrition/Vitamins/low_prenatal_vitamin_d_type_1_diabetes_0117120243.html
Study: http://diabetes.diabetesjournals.org/content/61/1/175.short


OmniBio Will Start another AAT Clinical Trial

OmniBio is testing AAT, an anti-inflammatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person don't make enough of it on their own.    They started with a 15 person, phase-I study, and about 11 months ago expanded to a 50 person study, which I would consider phase-II.  They just announced that they will start another study for type-1 diabetes and one for Graft-vs-Host disease.  That's good news, of course, but I'd be a little more excited if they announced the results from their initial 16 person study.

Previous blogging on AAT: http://cureresearch4type1diabetes.blogspot.com/search/label/AAT
Previous discussion of inflammation based cures: http://cureresearch4type1diabetes.blogspot.com/p/common-ideas-and-opinions.html
 
News article: http://www.marketwatch.com/story/omni-bio-to-conduct-new-human-clinical-trials-2012-01-13
Corporate web site: http://www.omnibiopharma.com/

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com
Mice cures: http://t1dcuredinmice.blogspot.com/

Zhao et al (Tianhe) Publish Successful Phase-I Results (in non-honeymoon diabetics)

In my opinion, this is big news.
It's the result of a phase-I study, published in BioMed Central's Medicine Journal (which is peer reviewed) by a group of researchers working at the University of Illinois at Chicago and in China.

What Did These Guys Do?

This trial was done on people with established type-1 diabetes.  Each person had a blood draw, and then a particular kind of immune cell was separated from the blood and specially processed.  The processing phase used umbilical cord stem cells, but not the patient's own umbilical cord.  (This was generic umbilical cord stem cells, not from the exact person being treated.)  The immune cells were then put back in the person.  The stem cells did not go into the person; they were only used for the external processing.

The goal was to teach the body's immune system to stop attacking beta cells.  The researchers refer to this as "education", and refer to the processing device used as an "Stem Cell Educator".

The treatment was done once and I think it took about 10 hours.  Patients were in the hospital for 2 days, but it's not clear to me if that was due to an over abundance of caution (this was a phase-I study, after all), or if it was really needed.  This trial was done at the General Hospital of Jinan Military Command (Jinan, Shandong, China).  The lead author of the paper is Yong Zhao, is an Assistant Professor at the University of Illinois at Chicago.

The patients averaged about 29 years old, and had had type-1 for an average of about 8.5 years.  Patients were followed for a total of 40 weeks, but most of the results data was gathered at 4, 12, and 24 weeks after the procedure.

The researchers divided their patients into three groups.  Group A (6 people) had some insulin production before treatment. Group B (6 people) had no measurable insulin production before treatment, and Group C (3 people) also had some insulin production  before treatment, but they got a "sham" (or placebo) treatment. 


What Results Did They Get?

There were no significant safety issues during the trial.

Average Daily Insulin Usage:
Group A's insulin requirement was down 38% at 12 weeks (from about 36 to 22 units/day).
Group B's insulin requirement was down 25% at 12 weeks (from about 48 to 36 units/day).
Group C's insulin requirements didn't change.

Note: earlier version of this blog had a typo in Group B's starting insulin units/day.  Fixed here.

Average A1C levels:
Group A started at 8.73 and dropped to 7.67 at 4 weeks and to 6.82 at 12 weeks (almost 2 points overall).
Group B started at 12.2 and dropped to about 10.5 at 12 weeks.
Group C started at 9 and was at 8.7 at 12 weeks.
Note: I consider a drop of 1 to be important, although some researchers consider even a drop of 0.5 as important.  Here we have drops of over 1.9 and 1.7.

Fasting C-peptide (ie. Body's ability to generate "basal" insulin at background levels)
All these numbers are average ng/ml, and are very approximate based on graphs in the paper.
Group A: Starts at about 0.35 and ends at about 0.8 at 24 weeks.
Group B: Starts at about 0 and ends at about 0.5 at 25 weeks.
Group C: Stays at about 0.4 at 4, 12, and 24 weeks.
Note: Non type-1 diabetics generally have a fasting C-peptide level between about 0.5 and 2.0.  The paper's authors felt that 0.6 was the lower bound of normal C-peptide in the population being studied.  So it is possible that Group A has moved into the bottom of the normal (for non-type-1 diabetics) range.

OGTT C-peptide (ie. Body's ability to generate "bolus" insulin in response to food)
All these numbers are average ng/ml, and are very approximate based on graphs in the paper.
Group A: Starts out generating 1 after a meal, at 4 weeks generates about 1.6, and at 12 weeks about 1.7.
Group B: Starts out generating about 0 after a meal, at 4 weeks generates about .05, at 12 weeks about 0.35, and at 40 weeks about 0.6.
Note: I don't know what "normal" is for this test, so can not compare either group to non type-1 diabetics.

The paper also contains data on immune system changes which the researchers felt showed significant improvement in autoimmunity.    I can not evaluate those results.

Also interesting, the researchers are very specific in saying that they think this study shows that beta cells do regrow, in people, if the immune system stops attacking them:

Notably, our clinical data provide powerful evidence that reversal of autoimmunity leads to regeneration of islet β cells and improvement of metabolic control in long-standing T1D subjects.

My take on all this data is that there is no question that the body is generating more of it's own insulin after this treatment than before.  And that happens in people who have had diabetes for a long time, and who are not generating any of their own insulin before treatment.  That's huge.  The results are large enough so that type-1 diabetics would see the improvement in their insulin usage and A1C numbers.

Discussion

Obviously, there is a lot of issues to discuss here:

Possible Conflict of Interest

I hate to start off with discussion of a conflict of interest, but in this case, the situation makes me nervous, so I'm discussing it first.  In the paper's pre-publication version, it says:

Competing interests 

The authors declare that they have no competing interests.

However, the unique and specialized equipment that they used in their clinical trial was manufactured by Tianhe Stem Cells Biotechnology.  This equipment was central to the clinical trial.  However, that company is connected to three of the authors (including both first and last authors).  Here is a quote from the University of Illinois web page:

Tianhe is a stem cell biotechnology company commercializing the inventions emanating from the labs of Drs. Zhao, Mazzone and Holterman within the Departments of Medicine and Surgery at the University of Illinois at Chicago. With operations in both Illinois and overseas, the Company is pursuing the application of stem cells for the treatment of autoimmune diseases.  Tianhe is initially pursuing the treatment of Type 1 diabetes through a clinical system which extracts the patient own stem cells and utilizes them to re-educate the patient’s faulty immune cells to prevent future immune response to the patient’s own insulin producing cell.    [from http://otm.illinois.edu/sites/all/files/files/otm-annual-reportseptember-1final.pdf]

Obviously, I don't know the exact financial details involving the University, Tianhe, and the three researchers, but I would like to see more details before I accepted the claim that the authors had no competing interests!  It certainly sounds like the researchers are testing equipment that they will make money off of, if it works.  On the other hand, if this relationship gets this research to market quicker, and the research helps people with type-1 diabetes, then I'm all in favor of it. :-)

Missing Data

There are a couple of obviously missing data points.  For example, Group A's 40 week post-meal C-peptide numbers are not reported.  And 40 week fasting C-peptide data is not reported for any group.  The trial design only collected insulin use and A1C data at 12 weeks, which is too bad.  I would have like to see it at 24 or even 40 weeks as well.

There are also a few other odditites.  For example: in Groups A and B (treated), about 2/3 of the patients are women, but Group C (placebo) is all male.  Also, the Group B A1C before treatment averaged 12.2, which is a lot higher than you would see in the US (I hope!)

None of this is particularly unusual for a phase-I trial; and none of it makes me nervous about the results.  It just makes me want to see data from a larger phase-II study.

Next Steps To Market

Getting a cure to market requires three things:
1. Scientific success.
2. Engineering and corporate success.
3. Regulatory approval.

This study is a solid, successful phase-I clinical trial.  No doubt (in my mind) about that.
Plus, it is the first time this has been used in people, as far as I know, and there are obvious ways to improve it.  More blood could be put through the machine.  The blood could spend more time in the machine.  It could be used repeatedly, etc.  The classic goal of a phase-II trial is to figure out the best dosing, and I think these guys are well positioned to do that.

There is a clear engineering path to market.  The "Educator" equipment is produced by Tianhe corporation, and I would expect that once the equipment is for sale, many doctors would be able to use it.  It sounds to me like there is a clear way to make money off this, and so I would expect that (if it works scientifically) Tianhe will have no problems getting funding and getting the corporate structure required to build a business around using their equipment to treat/cure type-1 diabetes.

As for regulatory approval, I think there are two paths forward.  The normal path to approval is a phase-II trial, and then two phase-III trials.  The already completed phase-I trial took about a year, I would expect the phase-II to be about that long, maybe a little longer, and phase-III to be still longer.  However, if they are successful and well funded, these guys could get to market in less than 10 years.  Of course, the next question is, what will they make it to market with?  Will the thing available be a treatment?  A cure?  A temporary cure?  Fewer long term complications?

There is a second, much faster, path to approval, called the "surgical procedure exemption".  I do not know all the details, but the FDA does not require that surgical procedures be proven "safe and effective" before a surgeon uses them.  Under this exception the FDA does allow some treatments to be sold without full approval, if those treatments involve taking something out of the body, processing it in some simple ways, and then putting it back in.  I don't know if this "educator" process would qualify or not.

I know some people are nervous about research done in China, and especially at a Chinese military hospital.  I think this is my first detailed blog post on research done in China.  I do want to point out that this trial has ethical approval from the review board at the University of Illinois at Chicago, and that it looks to me like the researchers followed US FDA standards in the trial, and international standards where applicable.  I don't have detailed knowledge of FDA requirements, but it does look to me like, even at this early stage, these guys are working to eventual US FDA approval.

News Coverage: http://www.medscape.com/viewarticle/756691?src=emailthis
Clinical Trials Record: http://clinicaltrials.gov/ct2/show/NCT01350219
Full Paper: http://www.biomedcentral.com/content/pdf/1741-7015-10-3.pdf

Some general information on C-peptide values:
http://www.diabeteshealth.com/read/2000/09/01/2020/interpreting-your-c-peptide-values/

A Personal Note
2011 was an awful year for following clinical trials aimed a curing type-1 diabetes.  We lost three phase-III clinical trials, and started zero new ones.  In phase-I and phase-II trials, the successes seemed small; the failures, great.   These results are a wonderful way to start 2012.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com/

New Blog: Cured In Mice! (And Other Blog News)

I'm experimenting with a second blog, which I'm calling:
Cured In Mice!  you can read it here: http://t1dcuredinmice.blogspot.com/
Although the formatting will change a little over the next few months.

My goal is to have one blog entry for every treatment reported to have cured or prevented type-1 diabetes in NOD mice, or any other animal.

Each entry will have the date the cure was reported, one or more links to news reports, press releases, or research papers, and maybe a paragraph on the cure, or quotes from the articles.  But I don't plan to put in analysis or discussion in those blog entries. I'm leaving comments open for now, but I really only want comments to note when one of these cures moves to a later stage of research.  I may close comments entirely in the future.

Each title will be of the form TREATMENT by DOCTOR at RESEARCH INSTITUTION.  Two examples:
Glyphosine by Michels at Barbara Davis Centre for Childhood Diabetes
Escapsulated Beta Cells by Nuvilex at SG Austria

I will use tags to keep track of the basic type of cure being reported.  For example, the tags "cure", "honeymoon", and "prevention" will describe when the intervention is effective.  There will be tags for the basic types of cure "encapsulation", "immune modulation" etc.  And tags for the animal involved (such as "BB rat", "NOD mice" or just "mice" if the exact type is not known.

Why a "Cured in Mice" Blog?

This blog exists because of frustration. My frustration at constantly hearing that type-1 diabetes had been cured in mice (again), but never hearing that it was cured in people.  My way of dealing with this frustration is to try to keep track of the number of times people cure type-1 diabetes in animals. After all, the first step to understanding something, is to catalog it.

At the very least, this blog will help readers keep track of how many mice cures are developed each year, what happens to them, and how long it takes to happen. I hope that the data found will fuel other types of "research into research" on type-1 diabetes.  It will also help track how long it takes to move from animal to human trials.  Whenever a human trial starts, I'll be able to go back to this blog, and see when the same thing was first successful in animals.  You can think of this blog as raw material for future research into type-1 cures in mice.

How You Can Help

If you hear of a cure for type-1 diabetes in any animal, then please shoot me a quick email.  All you need to do is put "Cured in Mice" in the subject line and put the URL where the news was reported in the email.  I can get all the information I need from there.  Don't worry if you think others have already sent it in.  I'd rather get extra emails than not enough.  I'm especially interested in research done outside the USA or reported in languages besides English.  (Because I don't read any other language, and get most of my news from USA-centric news sources, I'm much more likely to miss research that is reported on in another language or country.)

Getting Either Blog Emailed to You

If you're reading this on my blog web site, you can easily sign up to get these blog posts sent to you (either this "Cure Research" blog or the new "Cured in Mice" one).  Just enter your email address in the "FOLLOW BY EMAIL" box on the right.  In the past, I  had to have a Google email group for this, but that's a lot of work that I don't need to do any more.

If you are getting this as part of the Google group, please add your email (as above) and unsubscribe to the Google group.  I plan to shut down the Google group sometime in 2012.


Reminder About The Blog
There three ways you can help with this blog:
First, tell other people about it!  Heartfelt testimonials are the best advertising.
Second, tell me about any clinical trials you know about that are not already covered here.
Third, ask me questions that you have.  This tells me what I'm not explaining well, and where I need to put more information into my posts.


Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Two Essays On Progress

This blog posting consists of two separate essays on the nature of progress.  It is background for understanding forward progress on a cure for type-1 diabetes, but also for other types of medical research.

Engineering Progress vs. Scientific Progress

Many people tend to mix up science and engineering.  (They both use a lot of math, right?)  But in my mind it is very important to understand the differences.  English often doesn't have the right words or phrases to properly describe these differences, so it is hard to discuss them, but understanding them is very helpful in understanding type-1 cure research.  I believe that a lot of the frustration that people feel as they follow this research would be alleviated, if they understood better the differences between scientific progress and engineering progress.  Although even as we understand the differences, we also need to remember that curing type-1 diabetes is going to require both engineering progress and scientific progress.

Engineering progress is generally doing something you already do, but better.  Scientific progress is learning something you don't already know.  The most obvious difference, is that engineering work can be planned, even scheduled, but scientific breakthroughs can not.  Sure you can plan and schedule scientific experiments, but not their results.

My belief is that curing type-1 diabetes will require at least one major scientific breakthrough, and probably at least one major piece of engineering progress as well.  I don't think that engineering progress alone will cure type-1 diabetes.  (The only exception to this would be the artificial pancreas, if you consider that a cure.  I do believe that an AP can be created with just engineering progress.)

Why does this matter?  Well first, because some people believe that the key to curing type-1 diabetes is to set schedules (with deadlines) for researchers.  This is based on the idea that type-1 can be cured via engineering progress alone.  It is engineering research that benefits from schedules, deadlines, etc.

I was at a JDRF research symposium in San Francisco a few months back, and there was one particularly bombastic guy there, who was really pissed off that JDRF did not set schedules to cure type-1 diabetes, and have deadlines based on those schedules. This guy worked in the financial side of an engineering company, so he understood the important of schedules and deadlines to engineering progress, but didn't seem to understand that scientific progress was fundamentally different.  Or, maybe he thought that type-1 could be cured with engineering progress alone.

Another reason is this: engineering progress can (almost always) be assured by putting in money and time.  Money and time will solve just about any engineering problem.  And money is usually more important that time.  Putting in more money will solve almost all engineering problems quicker.  But that is not true of scientific progress.  Sometimes scientific progress simply can not be made, because the thing is impossible.  Sometimes forward progress needs a new understanding, which is based on luck or deep understanding or something else which can not simply be bought.  (Putting more money into it raises the chances that you will get the breakthrough you need, but you're just playing with probabilities.  Three is no predictability.)

Pushing scientific progress is much more a question of funding research in general, and making more researchers interested in working in that area, removing barriers to that kind of research, and making it easier (in general) to do that kind of research.  Basically, you can only make breakthroughs more likely, rather than try to fund and schedule a specific breakthrough.

As an example, if you have a car that can go 90 miles per hour, and extra money, you can make a car that will go 110 MPH.  You'll just put in a better motor, or better fuel, or make the frame lighter or something.  But if you have a particle accelerator that can speed particles to 0.9 times the speed of light, then no amount of money or time is going to make so you can push those particles to 1.1 times the speed of light.  (Because right now, no one knows how to make anything go faster than the speed of light.)  The first is a question of engineering progress, the second is a question of scientific progress.  You can solve the first with money, schedules, deadlines, etc.  But not the second; at least not in a simple minded way.

The difference between engineering progress and scientific progress is one of the reasons why I'm a lot more positive about developing a "closed loop" artificial pancreas, then stopping the autoimmune attack.  To put it bluntly: we already know how to build everything needed for an artificial pancreas.  It is just a matter of engineering progress until we get one that works (and political progress until the FDA approves it).  However, we do not know how to shut down the autoimmune attack.  It will require a scientific breakthrough (and maybe more than one) to do that.

The take home point is that engineering progress and scientific progress (sometimes called "breakthroughs") are fundamentally different.  The rules for one are completely different than the rules for the other.  Applying the truth learned about one, to the other, results in bad decisions and wrong conclusions.  And frustration.  Lots of frustration.  (As I said above, trying to applying deadlines and schedules, which help engineering progress, to scientific progress, is a classic example of this mistake.)

Finally, don't fall into the simple minded trap of thinking that science fuels engineering in a one-way direction.  Sure, scientific breakthroughs are productized and mass produced via engineering progress.  But in many cases, scientific breakthroughs are created based on tools which were previously created via engineering progress.  The process is circular: Engineers give scientists tools; scientists give engineers breakthroughs; engineers use those breakthroughs to create all kinds of things, including new tools.  The process repeats into the future,  which brings up my next topic:

The Distribution of Knowledge

This essay is motivated by the following two quotes:

The future is here, now.  It is just not evenly distributed.  [r1]

The world is flat. [r2]

Now these two quotes express opposite ideas, a duality [d1].  The first says that there are differences between what is available here and what is available somewhere else, and the second says that things available elsewhere are also available here.  They are both supposed to apply to goods, services, and (most importantly) knowledge.  So which is right?

The idea behind the first quote, is that new discoveries take time to become available everywhere. This delay is partly caused by the speed of communications and partly by differences in wealth.  For example, 1000 years ago a discovery made in South America would never be available in Europe, because there simply was no communications between the two of them.  Even 100 years ago, discoveries made in far flung places, or in unusual languages or cultures might take decades to become well known in other parts of the world.  However, it is also clear that today and in the future, more and more, "The world is flat." [r2]  Discoveries made in one place by one culture are rapidly available to everyone.  Although there are still differences between what the rich can get and what the poor can get.

Why does this matter to type-1 diabetes research?  Because, especially right after diagnosis, many people become interested in type-1 diabetes research because they believe that somewhere, someone has already cured type-1 diabetes (or is about to), and the news just hasn't reached them yet.  They are very hopeful that the future cure for type-1 diabetes is already here, it is just in some amazon jungle tribe's traditional knowledge, or some clinic owner in Germany, or the back of some Ivy League / big pharma research lab, etc.  Even years after they realize that it's not so, they continue to hope (and sometimes make poor decisions based on that hope).

Even worse, there are people who actively prey on that line of thinking.  They say "I know how to cure it, and the only reason you haven't heard of it is because of some grand conspiracy or simple lack of communications, but in any case, if you give me your money, I already know how to cure you."  These people are using other people's belief in the "not distributed evenly" idea to create a false hope.

In my opinion, the truth is that the first quote used to be true.  Knowledge has been unevenly distributed for all of humanity's existence, except the very last few years.  This belief forms the foundation to almost everyone's thought process.  Many people believe it very deeply without even thinking about it.   But today, the second quote is almost always true, and shortly the second quote will always be true [d2].  People will make better decisions if they understand how untrue that first quote is, when it describes knowledge, right now.

Today, with the internet, and English as a common language of both science and engineering, knowledge spreads more quickly and more evenly than at any time in the past.  So it is now almost impossible to have knowledge available in one part of the world, that is not available in all the rest as well.

Extra Discussion and References

[d1] Dualities are not choices between right and wrong answers.  They are inherent trade-offs without a single correct answer that force us to learn about the underlying situation, in order to make the best decision about a situation.  Wikipedia puts it this way: "a single conceptual unit that is formed by two inseparable and mutually constitutive elements whose inherent tensions and complementarity give the concept richness and dynamism"  http://en.wikipedia.org/wiki/Duality_%28CoPs%29

[d2] The only exception is cost.  The rich will always be able to afford things that the poor can not. However, especially in the context of a cure for type-1 diabetes, this is not likely to be a huge issue.  See my previous post: http://cureresearch4type1diabetes.blogspot.com/2011/11/future-cost-of-type-1-cures.html for more discussion of a cost of a cure

References

[r1]  William Gibson, author of the most forward thinking book of the 20th century: Neuromancer.

[r2] This quote, with this meaning, is attributed to Nandan Nilekani and made famous by Thomas Friedman (Pulitzer prize winning journalist) who wrote a book: The World is Flat, commenting on the lack of barriers to goods, services, and knowledge moving around the modern world.


Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com

Artficial Pancreas Updates

Here are a couple of recent updates on Artificial Pancreas testing and development. Remember that not everyone considers an AP a cure, but here is an update no matter if you consider it a better treatment or a cure.  Also there are a couple of "odds and ends" on other topics at the end of the posting:

Medtronic Starts Testing Veo technology in the US

Veo is a "stage 1" artificial pancreas, meaning it is an integrated pump, CGM device which has one small piece of intelligence in it: it will automatically turn off basil insulin if the BG numbers have been too low for too long.  It is the very first baby step to a commercial artificial pancreas.  They've been selling it commercially in Europe for years, and just got permission to start testing it in the US.

I could not find the clinical trial record for this study, so I'm basing my information off the press release.
    First, the study will be "pivotal" which usually means phase-III.
    Second, it will be an at home study, which is another sign that they are close to FDA approval.
But I do not know how large this test will be, how long it will run, or when results will be expected. Although device tests are often much quicker than drug tests, so these tests might only run for a few months, but they will still need to recruit a lot of people, which takes time in itself.

Press release: http://wwwp.medtronic.com/Newsroom/NewsReleaseDetails.do?itemId=1319745760295&lang=en_US
News coverage: http://medgadget.com/2011/11/medtronics-low-glucose-suspend-technology-brings-insulin-pump-closer-to-artificial-pancreas-functionality.html 

Artificial Pancreas Operating on Cellphone Tests Successfully
Type-1?  These guys got an app for that!  :-)

This is a university research group at the University of Virgina, which is running an aggressive artificial pancreas project.  They have completed four clinical trials, and  are recruiting for six more:
http://www.clinicaltrials.gov/ct2/results?term=Kovatchev

This specific trial involves 15 people (5 each Virgina USA, Padua Italy, Montpellier France), who will spend two nights in a hotel and the day between at the hospital.  This is a pilot study to see if it feasible to run a larger study.  I would consider this a phase-I trial.  The software uses standard CGM and pumps, but the thinking part of the artificial pancreas runs on a Android phone.

I like this approach for a number of reasons.  First, I think it will make it easy to make incremental improvements to the AP software.  It is much easier to download a new app, than to get a new pump.  Second, the easier it is to develop AP software, the more people will do it, and the faster development will move forward.  Third, my gut feeling is that anything that runs on a computer now (such as the Sansum software being tested in the next two trials) will be able to run on a smart phone in a few years.   Fourth, pumps tend to have crummy screens, buttons, and user interfaces in general, because the companies focus on the "functional" parts, such as the pump.  However, smart phones have great screens, buttons and user interfaces because those are very important for their success.  So any AP software running on a smart phone will get a better user interface "for free", as compared to anything running on a pump like device.  Fifth, smart phones are naturally networked which I think can lead to improved quality of care.   I look forward to a time when your smart phone will power your AP, and maybe once a week it will upload a week's data to a central computer ("in the cloud") which will run lots of data analysis on it, and then download some improvements to your AP.

Note: In real life (when not writing this blog) I'm a software engineer (actually a "technical lead") and the software I'm working on right now is an app for a smart phone, so I do know something about app development.  The software I develop is not part of the medical industry.

They expect this study to be completed by September 2012.  (Remember: device studies are often quicker than drug trials.)

Clinical trial records (one per site, I don't know why):
http://www.clinicaltrials.gov/ct2/show/NCT01447979
http://www.clinicaltrials.gov/ct2/show/NCT01447992
http://www.clinicaltrials.gov/ct2/show/NCT01470807

News coverage: http://www.nbc29.com/story/16105702/artificial-pancreas-operating-on-cellphone-tests-succesfully
http://www.healthcanal.com/medical-breakthroughs/23649-Artificial-pancreas-real-world-success-for-diabetes-patients.html

Phillip Artificial Pancreas Trial

This artificial pancreas is called MD-logic and this it it's second test on people (that I know of).  This trial is 18 teenagers, and is being done in a camp like setting in Isreal, for at least 24 hours.   The MD-Logic device comes in two types, but the one being tested here is the "SC" system which tests sugar levels just under the skin, and doses insulin just under the skin.  So it is like a current CGM system and a current pump system, connected  via a laptop computer.  (For this trial the laptop is being carried around by the patient, all the time.)  This "SC" system has been previously tested on 4 adults, in 8 hour sessions in a hospital.  The results of the previous trial was BG levels between 92 and 150, which in my opinion is very good.

MD-Logic also comes in an "IV" system, which measures sugar levels directly in the blood stream, and also doses insulin directly in the blood.  In theory this should lead to more accurate BG readings and faster insulin effectiveness.  This version has only been tested on pigs, for 1 hour at a time.  However, during those experiments it kept BG levels between 80 and 130, which I believe is the same levels as found naturally in a non-type-1 diabetic.

I think this is the clinical trial record for this study (if not it is for a closely related trial):
http://www.clinicaltrials.gov/ct2/show/NCT01308164

Note that some articles have claimed that this is the first trial outside of a hospital, but I don't think that is correct.  I think there have been two or more previous trials outside of hospitals, including the one right above.

Abstract of earlier research: http://www.ies.org.il/abstracts09/Stem%20cell%20in%20Diabetes%20Mellitus%20symposia-HW103-106.pdf
News coverage: http://asweetlife.org/a-sweet-life-staff/featured/the-loop-has-closed-the-artificial-pancreas-program-comes-to-life-in-israel/21042/

I'm not 100% sure, but I think that these guys are using the same Sansum Diabetes Research Institute software as the Beck group below.  I believe this team is also participating in the Beck trial below.

Beck In-patient Evaluation of an Artificial Pancreas

This is a 50 person study, which should be completed by March 2012, so quite soon.  (It started back in March 2011, and I'm sorry that I did not blog on it back then.)  It uses a DexCom CGM, an Omnipod pump and a laptop.

For those in the bay area: Drs. Buckingham and Wilson at Stanford are involved.  There are also sites in Virgina, Denver, Padova Italy, Montpellier, France, and Israel.

I believe that the "Phillip" trial listed above, is using the same basic software, but in a more aggressive setting.  The "Phillip" trial is camp like, while "Beck" is in a hospital.  On the other hand, "Beck" is larger and multi-site, while "Phillip" is smaller and only one site.  "Phillip" is on children, "Beck" on adults.  Finally, "Beck" is over half way done, while "Phillip" is just starting.


The FDA's New Guidance for Artificial Pancreas Testing

Last Thursday the FDA issued new guidance for artificial pancreas testing, and several readers have asked my thoughts on it.  As you read my opinions, remember that I'm not an expert in understanding FDA technical documents, and it is a very specialized field with much specific knowledge needed to do a good job.   

My general opinion is that FDA guidelines don't matter.  What matters is how they are interpreted in actual use.  So reading a guideline is nice, but the important thing is what happens when the FDA actually uses that guideline to approve or delay a medical device.  So my basic reaction to this news (that the guidelines have been released) is to shrug and wait for them to be used, and see what happens then.  The guidelines are a necessary step forward, but can't be evaluated on their own merits.  Not issuing them delays the process, and now that delay has ended, and that's a very good thing, but it says nothing about the quality of the guidelines.

I did read parts of the guidelines, and skim other parts.  It's tough going, but I have the following comments based on my understanding of the guidelines.  These are all improvements over the current rules, and point 2 especially would be a huge improvement:
1. There need to be three phases of testing (much like new drugs), and the first is usually in a hospital, the second usually in a camp or similar controlled environment, and the third in the real world.
2. There seem to be two alternate paths to approval, one being testing that the device is better than current methods ("Superiority"), and the other is that the device is not worse than current methods ("Non-Inferiority").  Either path would lead to device approval, but with different marketing claims being allowed.  Proving superiority would allow marketing literature saying that the device was better, and so on.  If A1c is used as the primary end point for the phase-III study, then showing a 0.4 improvement would be proof of superiority. 
3. Computer simulations (referred to a "in silico" testing), may be used to replace some animal testing, but is not a replacement for human testing.
4. A1c data or BG data from a CGM may be used as primary end point data, although the FDA recommends A1c data. 
5. There is a lot (my opinion) of flexibility in the secondary data that an applicant may choose to collect in their study.
6. In some cases, trials from other countries can be considered in approving devices.

FDA: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/HomeHealthandConsumer/ConsumerProducts/ArtificialPancreas/default.htm
News coverage: http://www.cbsnews.com/8301-500368_162-57335258/new-fda-guidelines-for-testing-artificial-pancreas/
http://yourlife.usatoday.com/health/story/2011-12-02/FDA-speeds-development-of-artificial-pancreas-systems/51579288/1
JDRF's PR: http://www.sacbee.com/2011/12/01/4093655/jdrf-encouraged-by-draft-fda-artificial.html

Unrelated News Items, Which I Found Interesting

Measuring Pre-Type-1 Diabetes

Quote from the press release:

[Lead researcher Kevan C. Herold and team] at Yale University have developed a method to detect and measure the destruction of beta cells that occurs in the pancreas by measuring DNA expression in the blood. The destruction of beta cells leads, over time, to type 1 diabetes. 

If this research pans out, it is likely to have two large and quick effects on research aimed at curing type-1 diabetes.  First, it will make it easier to test treatments aimed at preserving or regrowing beta cells.  Right now, it is hard to tell if these work, because we generally measure them indirectly (via C-peptide production).  This might allow us to measure it directly, and see if the treatments are working a little, a lot, or not at all.  Second, it might make it easier to prevent type-1 diabetes, by agressively treating type-1s right when the beta cell destruction starts.   Right now, we know when it is about 80% complete (that's when type-1 is diagnosed), and we can see when antibodies start to be generated (but that might be too early).  This gives us another way to intervene early for purposes of prevention, if not cure.

Press release: http://media-newswire.com/release_1162305.html

Overview Article on Status of a Cure

The following article is worth a read.  It discusses the recent failures of CD3 based clinical trials, and the general state of research into a cure:
http://www.endocrinemetabolic.com/blog/reset_clock_on_type_1.pdf

More Evidence that "Dead in Bed" is Slow

In my previous post on "Dead in Bed", one of the points I made, very briefly, was that type-1 diabetics who died in their sleep did not "spike low".  They did not have really low BG for a really short period of time before dying.  Quite the opposite, in the one case history presented there [r13], the person was low for many hours before dying.  The study below is a similar one, but it covers four people who had seizures.  These people did not die.

The take home point, is that three of them had low BG levels for four hours before their seizure, and the forth for over two hours.  That suggests to me that a low BG cut off feature would have plenty of time to work and prevent seizures (and eventual death).  

Full paper: http://care.diabetesjournals.org/content/31/11/2110.full

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com

Dead in Bed: What is the Chance?

Note: this posting was edited for clarity on Dec-24 .
Warning: this posting deals entirely with the worst side effect of type-1 diabetes: death.
Please do not read this posting if discussion of death upsets you.
Also, if you are a brittle type-1 diabetic or the relative of one, then [r12] will be particularly shocking.  Please read the entire discussion with that reference, if you read any at all.
Some people may find [r13] particularly upsetting, as it deals with a specific death, rather than statistical deaths in general.

The r-numbers in square brackets [r1] refer to references which are discussed throughout the post, the d-numbers [d1] to extra discussion at the bottom of the post. 

Recently, there was a lot of shock and horror when JDRF published an ad which said that for a type-1 diabetic the chance of dying of low blood sugar was about 5% over a lifetime.  So in this blog posting I'll examine the data on "dead in bed" to see if 5% is the correct rate.  Obviously, this posting is not about my regular topic: clinical trials aimed at curing type-1 diabetes.  But it is a subject important to everyone near to type-1 diabetes, and I wanted to see if that 5% number is true.

I don't know if anyone has said this before, but if not, I'm saying it now:

"There is never enough data to convince someone of something that they don't want to believe."

My one paragraph summary: there is no doubt that for type-1 diabetics who die young (ie under about 40 years old), over 5% of these deaths are due to hypoglycemia (low BG).   All the recent studies show this.  I could not find any data at all to come to a conclusion about the death rate for type-1 diabetics older than that. Since the data we do have is over 5%, I think 5% is a conservative estimate, although the lack of data for older diabetics does leave room for speculation that it is lower, there is no data to suggest that it is lower.

This posting is in four sections:
1. Some background information and discussion about how to measure death.
2. A review of the studies that JDRF referred to in their follow-up email as supporting the 5% number.
3. A review of other available studies, from my own research.
4. Some discussion on the social and political importance of this data.

Background Information

Measuring Death is Harder than you Think

Measuring how type-1 diabetics die is a lot harder than you might think, with unconnected medical records, like the US [d1]. The obvious thing to do, is to select a group of people, wait for them to die, and record how they died. However, you need to wait for them to die, so the data is available an entire generation after you selected the people. You could also do this "in reverse", research everyone who dies in a given place, and find out which ones have type-1 diabetes, and then record how they die. To do this for 300 type-1 diabetics, you'll need to research about 90,000 people who die just to find the 300 who have type-1 (remember only 1 in 300 will have type-1). That's a problem, too. A third way to do it is to follow many people of different ages, and then splice the data together grouped by age, to get a chance of death over an entire lifespan. But that requires following a lot of people, in several different groups, and it's not easy, either.

But none of these techniques are going to give you quick, up-to-date, and easy-to-get information on how type-1 diabetics die.

To make matters worse, not all "dead in bed" cases are hypoglycemia[d2,r10], and in many cases, especially in the past, these were tracked as sudden, unexplained death (or similar) but not generally considered a side effect of diabetes.

Many of the studies done in the past reported on "chronic complications" of type-1 diabetes (things like heart attack, loss of limbs, etc.) and "acute complications" (either low BG or high BG / ketoacidosis).  But they did not provide data on the number of low BG related deaths, just on all acute complications combined.

Finally, and perhaps most horribly, some researchers have referred to "dead in bed" or hypoglycemia as "insulin overdoses" or "drug misuse".  This has the effect of blaming the type-1 diabetic for their own death, or maybe blaming their doctor for prescribing too much insulin.  In any case, if a researcher had the choice of listing death as "insulin overdose" or "unknown cause of death" which did you think they did?  But then the true cause of death is lost from later analysis.

These issues have in the past lead to an under counting of deaths caused by hypoglycemia, but they provide little help in determining what the rate actually is.

A Review of JDRF's Sources

A quick summary of the data is as follows: two of JDRFs sources were very similar, and written by the same person, and used a total of 5 studies to estimate the 5% number.  See the quote under [r2] below.  Basically they showed that older studies had 2%-4% numbers and newer studies had 6%-10% numbers.  For reasons described above, I agree with JDRF that the new studies should be given more weight.

Another study that JDRF cited was the DCCT trial.  This is a large, recent study on the complications of type-1 diabetes.  This well respected study is commonly cited when researchers need data on rates of complications.  I suspect it has been used dozens, if not hundreds of times in the years since it was published.  It found a rate of 6%.

Below are listed the 9 sources that JDRF referred to in their email as supporting their 5% number:

[r1] Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008;57(12):3169?76.
full paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2584119/
This paper came to very similar conclusions to the one below, based on the same underlying research, and done by the same person, so see [r2] for details.

[r2] Cryer, PE. Hypoglycemia in Type 1 Diabetes Mellitus. Endocrinol Metab Clin North Am. 2010. 39(3): 641-654.
full paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923455/?tool=pubmed

Early reports suggested that 2% to 4% of deaths of people with diabetes are the result of hypoglycemia [r1][r16]. More recent reports indicate that 6% to 10% of deaths of people with T1DM are caused by hypoglycemia [r7][r8][r9]. Regardless of the exact rates, the existence of iatrogenic mortality is alarming.

[r3] Cryer PE. Death during Intensive Glycemic Therapy of Diabetes: Mechanisms and Implications. Am J Med 2011 124(11):993-996.
No abstract or paper available, still in process of being printed.

[r4] Deckert T, Poulsen JE, Larsen M. Prognosis of diabetics with diabetes onset before the age of thirty-one. I. Survival, causes of death, and complications. Diabetologia. 1978;14:363-370.
No abstract or paper available to me.

[r5] Tunbridge WMG. Factors contributing to deaths of diabetics under fifty years of age. Lancet. 1981;2:569-572.
No abstract or paper available to me.

[r6] Laing SP, Swerdlow AJ, Slater SD, et al. The British Diabetic Association Cohort Study, I: all-cause mortality in patients with insulin treated diabetes mellitus. Diabet Med. 1999;16:459-465.
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/10391392
Neither abstract had data on low BG deaths, and paper was not available to me.

[r7] Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 2007;356(18):1842?52.
Full paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701294/

A total of 1144 patients with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study were examined on entry to the DCCT (at mean age 27 years) and a mean of 18 years later with the same comprehensive battery of cognitive tests.

Of the 53 deaths during the DCCT and the EDIC study, 3 were attributed to hypoglycemia ...[So a 6% rate.]

[r8] Feltbower RG, Bodansky HJ, Patterson CC, et al. Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes: results from the Yorkshire Register of diabetes in children and young adults. Diabetes Care 2008;31(5):922?6.
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/18285550

A total of 4,246 individuals were followed up, providing 50,471 person-years of follow-up. Mean follow-up length was 12.8 years for individuals aged 0-14 years and 8.3 for those aged 15-29 years.  ...   A total of 47 of 108 deaths (44%) occurred from diabetes complications, 32 of which were acute and 15 chronic. [

The [r9] study below found that about 30% were acute and about 10% were low BG, so if that ratio is true for this study as well, then this study would also find about 10% death rate from low BG.

[r9] Skrivarhaug T, Bangstad HJ, Stene LC, et al. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologia 2006;49(2):298?305.
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16365724
Full paper: http://www.springerlink.com/content/f932481234766352/fulltext.pdf

All Norwegian type 1 diabetic patients who were diagnosed between 1973 and 1982 and were under 15 years of age at diagnosis were included [1,906 people]. Mortality was recorded from diabetes onset until 31 December 2002 and represented 46,147 person-years. The greatest age attained among deceased subjects was 40 years and the maximum diabetes duration was 30 years.

This paper found that about 10% of the people who died, died of low BG.

A Review of Other Sources

When summarizing research papers, the biggest single source of bias is to only include papers which support your position in the list of papers summarized.  So, to see if that happened, I did my own search of the literature, using Pubmed, ClinicalTrials.gov and Google Scholar as my primary sources.
My summary of these other sources, is that most of them do not provide directly useful data, but that the data they do provide does not conflict with the 5% number from the JDRF ad.

[r10] Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16186267
Diabetes Care. 2005 Oct;28(10):2384-7.
Mortality in childhood-onset type 1 diabetes: a population-based study.
Dahlquist G, Källén B.
Mean age at death was 15.2 years (range 1.2-27.3) and mean duration 8.2 years (0-20.7).

Seventeen diabetic case subjects were found deceased in bed without any cause of death found at forensic autopsy. Only two of the control subjects died of similar unexplained deaths.  In my opinion, this shows two things: first, that most "dead-in-bed" cases are acute complications of type-1 diabetes, but also that a few are not.  This makes the accounting harder to do.

[r11] Full paper: http://www.ncbi.nlm.nih.gov/pubmed/21903695
BMJ. 2011 Sep 8;343:d5364. doi: 10.1136/bmj.d5364.
Time trends in mortality in patients with type 1 diabetes: nationwide population based cohort study.
Harjutsalo V, Forsblom C, Groop PH.
Key table: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169676/table/tbl4/

This paper found about 19% (very roughly) died of acute complications.  If the same 1/3 ratio seen in [r9] is also true here, that would result in about 6% of deaths caused by low BG.  However, this paper separated alcohol/drug related acute events and those unrelated.  About 40% of the acute deaths were related to alcohol or drugs.  I think that is important to remember.

[r12] http://www.ncbi.nlm.nih.gov/pubmed/21285231
The outcome of brittle type 1 diabetes--a 20 year study.
Cartwright A, Wallymahmed M, Macfarlane IA, Wallymahmed A, Williams G, Gill GV.
Department of Diabetes/Endocrinology, University of Liverpool, Liverpool L9 1AE, UK.

This was the most emotionally horrifying paper I came across.  It was a small (33 person) study focused on brittle diabetics, the ones most likely to die from low BG.  They found that 20% of the deaths were caused by low BG, and that the type-1 diabetics who started out brittle (by their definition) had a death rate of 50% (!) over a 20 year period.  At the end of the 20 year study, none of the surviving patients remained brittle.  A very depressing result, but I don't think the data applies to most diabetics.  But it certainly makes me understand why brittle diabetics would be willing to have transplantation surgery including rest-of-their life drug treatments.  According to this study, the alternative is a 50% chance of death, and many chronic complications. 

However,  I later came across this follow on paper:
http://onlinelibrary.wiley.com/doi/10.1002/pdi.1630/abstract
which suggested that some of the type-1 diabetics in the previous study were brittle because of psychological issues or a lack of training.  The exact quote was this:

Most [surviving type-1 diabetics from the previous study] attributed their previous instability to life stresses and/or inadequate diabetes-related education. Two (20%) admitted to inducing dysglycaemia by therapeutic interference. ... None of the survivors was actively brittle, and most attributed resolution of brittleness to positive life changes.

[r13] Abstract: http://www.ncbi.nlm.nih.gov/pubmed/19833577
Confirmation of hypoglycemia in the "dead-in-bed" syndrome, as captured by a retrospective continuous glucose monitoring system.
Endocr Pract. 2010 Mar-Apr;16(2):244-8.
Tanenberg RJ, Newton CA, Drake AJ.

These researchers were recording CGM data (not monitoring it in real time!), from a patient who died of hypoglycemia with the monitor attached.  They were able to provide absolute proof that, at least some, "dead in bed" cases were directly caused by low BG.

For me, the most interesting data from this case, was that this person did not "spike low".  It is not that he suddenly dropped to a very low BG, and then died.  Nor is it that he dropped low, and then quickly died.  He was low for hours before death.  I suspect that his body was doing everything it could (glucagon, etc.) to try to keep the BG up.  The CGM was alarming repeatedly.  But after hours of keeping BG levels above fatal levels, the body simply could not do this any more, and the person died.

[r14]  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1060170/?tool=pubmed
Abstract did not mention % of deaths caused by low BG, but more than 90% of the people in this study were type-2 diabetics who were treated with insulin.

[r15] http://diabetes.niddk.nih.gov/dm/pubs/america/pdf/chapter13.pdf
H. Fishbein and P. Palumbo, "Acute Metabolic Complications in Diabetes," in Diabetes in America (Bethesda, Maryland: National Diabetes Data Group, 2nd ed. (1995) ch. 13, p. 283

Chapter in a book, but no specific information on prevalence of low BG as cause of death.

[r16]  Cryer PE. Pathophysiology, Prevalence and Prevention. American Diabetes Association; Alexandria, VA: 2009. Hypoglycemia in Diabetes.

Some Discussion

JDRF seems to have relied on several papers published by Dr. Cryer to develop their 5%.  His published record of research on the causes of death of type-1 diabetics goes back at least as far as 1990, and he has published a wide range of papers on this subject.

Why Publicize the 5% Number? 

To be blunt, because it is the only way to get the FDA to do their job. As I describe the situation, please remember that I'm speaking only for myself, and these are my opinions based on the (indirect) information available to me: The FDA is supposed to approve devices because they are scientifically shown to be safe and effective.  However, in this case they are simply refusing to do so [d4].  Insulin pumps with automatic shut offs for low BG conditions were approved in Europe years ago, and have been actively used there (by large numbers of people!) for at least two years.  There is no question about the safety or effectiveness of these systems.  Never the less, the FDA refuses to approve them here.  Luckily, the FDA, being a political agency, is subject to political pressure, and I assume that is why JDRF is publicly pointing out that the result of the FDA's lack of approval is death.  I very much wish that the FDA would do it's job based on the scientific data showing safety and effectiveness, but they aren't.  So this sort of pressure is the only other option available.

BTW: If anyone who works for the FDA or has first hand knowledge of the approval process for automatic shut off insulin pumps: I would very much like to talk to you about what IS happening.  Send me email, and I'll send you my phone number.

And remember, refusing to approve a safety cut off for low BG levels in a pump, has the effect (at least short term) of stopping all movement on a commercial artificial pancreas in the US.  Every pump manufacturer in the world knows that if the FDA won't approve a low BG cut off, they surely won't approve anything more advanced either.  So the best treatment likely to be available in the next decade or so, is being held hostage by FDA unreasonableness.  There is a lot at stake here.

Late breaking news: in the last day or two, the FDA has announced new guidelines for testing closed loop / artificial pancreas systems.  I'll see if I can put together a blog on that news in the near future.  Better late then never, I guess.  Hopefully better guidelines rather than worse ones.

Non-Data Based Arguments That the 5% Number is Wrong

I was a little surprised (but I shouldn't have been) about some of the arguments that people made that the 5% number was wrong, that was not based on data at all.  I discuss two of those arguments -- very briefly! -- below.

I never heard that number before, so it must be wrong. [d5]    Many people are uneasy with discussion about the possible death of themselves or their children.  There is a lot of pressure not to talk about death as a side effect of type-1 diabetes.  So it is not at all surprising that there is not as much talk about it as it deserves, and hence, many people have not heard about it before.  But that is no reason to assume, when it is talked about, that the data is wrong.

Also, as long as doctors thought of low BG as insulin overdose or as drug misuse, then they also may choose not to talk about it, since they will end up blaming the dead, or the dead person's doctor.  So, both doctors and patients (including relatives of patients) had good reasons not to talk about "dead in bed", so some people are a little surprised to hear about something they are not used to hearing about.

That number only applies to relatively young type-1 diabetes (under 40, for example), and doesn't apply to all because most die when they are older than that.  This is not a groundless argument, because the data we have is for people younger than 40, but most people die when they are over 40.  However, it requires a lot of speculation.  We have data for people under 40 and the more recent data shows a higher rate than 5%.  We have no data for people older than 40, so some people hope that the over 40 number death rate might be very different from the under 40 death rate, and therefore that the entire-life chance of dying from low BG might be lower than 5%. For me, that's not reasonable doubt, that's just speculation. Maybe "wishful thinking" is a better phrase to describe it. I do think that running a study focusing on older type-1 diabetics would be a good thing, and would fill an important hole in the data. But I do not think it is reasonable to speculate that the data we don't have is different from the data we do have.

Why Talk about Scary Data? / Why Present the Data so Strongly? 

When this data was presented several people felt it should be muted or toned down.  I think that is largely a matter of personal taste.  Do you get more from being quiet and polite or being loud and scary?  Different people will disagree and this is reasonable.  For my part, I think the JDRF and the the pump/CGM industry has been taking the quiet and polite tack for years, and it doesn't seem to be working.  So I'm cool with the loud and scary tactic at this point.

Obviously death is the worst possible side effect of type-1 diabetes.  If we are not prepared to get loud and scary about that, then what? There is no question in my mind that we are looking at the cause of about 10% of the type-1 diabetics who die young (under 40).  That's huge all by itself, without even starting to discuss 5% over a lifetime.

More Discussion and References

[d1] I mean records which are scattered and hard to review or use for large scale studies.  In the US, we have death records, but no way to link them to health records.  If a patient changes doctors or health plans, their records become separated, and so on.  There is no place to look for a person's entire health history.

[d2] In the 1990s co-worker of mine (in his 20s) was found dead-in-bed, and he did not have type-1 diabetes.  It was very mysterious and ominous.  See [r10] for a little more data.

[d4] I don't follow FDA process closely myself, but my understanding is that the FDA started out saying that in order to be approved, an automatic cut-off system had to show that it reduced low BG events by 10% compared to MDI.  Obviously, this is NOT showing safe and effective, this is showing better than the competition, so already a groundless requirement for the FDA to make.  However, when the company actually presented the studies to the FDA, to get them reviewed prior to starting, the FDA changed it's mind, and decided that the company had to show 30% decrease!

The European safety agency actually did what the FDA was supposed to do, they required tests that the shut off feature did not cause any problems (safety), and that it worked at least as well as current pump technology (effectiveness) in terms of low BG issues.

[d5] The speaker thinks that because they themselves have never heard something, then therefore it must be false. Or the speaker thinks that something doesn't make sense to them, so therefore it must be false. The first is very dangerous because it assume a person is all-knowledgeable, so if they haven't heard it, it's not true. The second is dangerous because it assumes that the truth always makes sense (or is logical), and it doesn't.

The soundtrack for this blog entry is Juke Box Hero (Any Live Version) by Foreigner as found on YouTube.com: http://www.youtube.com/watch?v=EAUOx4lpt24

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Blog: http://cureresearch4type1diabetes.blogspot.com