Saturday, December 24, 2011

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

Thursday, December 8, 2011

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

Friday, December 2, 2011

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