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"

[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: for more discussion of a cost of a cure


[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.

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:
News coverage: 

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:

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):

News coverage:

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):

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:
News coverage:

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.

News coverage:

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:

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:

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:

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.

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:
    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:
    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.
    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:
    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.
    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.
    Full paper:
    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, 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:
    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:
    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:

    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.

    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:
    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:
    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.

    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.

    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

    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. 

    Sunday, November 27, 2011

    Andromeda's DiaPep277 Succeeds In Phase-III Trial

    ... but what does that mean? 

    Good News First

    This was a big (450+ people) study, and phase-III, so late in the processes of commercialization.  The treatment was DiaPep277, which is a peptide (a short protein) which is related to a naturally occurring protein called "heat shock protein 60" or hsp60.  The treatment is one under-skin injection every 3 months.  People were followed for 2 years.  The study was blind, random assignment; half got the treatment, half the placebo.

    DiaPep277 works by increasing the activity of regulatory T cells (especially Th2 cells), which serve to control the autoimmune attack on beta cells in the pancreas.  Earlier research described the mechanism this way: hsp60 is a protein found in the pancreas and very similar to hsp65, which is found in microorganisms.  Your autoimmune system gets mixed up between hsp65 (sign of foreign invasion) and hsp60 (naturally there), and attacks the beta cells in your pancreas.  DiaPep277 is part of the larger hsp60 molecule and teaches your immune system not to attack.  The idea is similar to giving people tiny amounts of peanut protein to wean them off of peanut allergies. [r3,r4]

    The important pieces of news from this study are:
    1. The primary outcome for this was C-peptide production.  Measuring C-peptide is the same as measuring the body's production of insulin[d1].  The people who got the treatment generated (on average) 0.949 nmol/L/20 minutes more, which is 23.4% more than the untreated group. That was statistically significant.  But remember that type-1 diabetics generate very little insulin, so even a tiny bit more will cause a big percentage change.  
    2. Untreated honeymoon diabetics loose their ability to generate insulin as the disease progresses.  People treated with DiaPep277 also lost this ability, but it happened more slowly, so that at each point in time, the treated group generated more of their own insulin as compared to the untreated group.  Some of the news coverage refers to "preserving insulin production" but it is important to remember that insulin production was not preserved at the same level as when treatment started.  Instead, production was higher in treated people then in untreated people. It's a big difference.
    3. A secondary outcome was lower A1c numbers in the treated group.  The company did not report average A1c numbers [d2], but they did say that 45.5% of the treated group was below 7, but only 35.7% of the untreated group was that low.  This suggests that the extra insulin produced was useful, and was lowering A1c, and was having a positive effect on the body. 
    4. The "initial safety data also indicate that DiaPep277 was well tolerated", which means no serious side effects, which is always a good thing, and consistent with earlier testing.  This drug never had a hint of safety issues, that I know of.
    5. Shlomo Dagan, CEO of Andromeda (the developer of the drug) said "I estimate that that the drug will be on the shelf by the end of 2014" (but this was quoted in Hebrew, which I don't understand, so I'm relying on a translation into English).  But I think he's wrong about that.  To get approved, a drug needs two trials.   The second phase-III trial is supposed to finish enrollment in 2012, and it's a 2 year treatment program, so that study finishes in 2014.   Then there is a year or two for marketing approval, so I'd estimate approval in 2015 or 2016, assuming further analysis of this trial is successful, and the second phase-III trial is also successful.
    You can read more about Andromeda here:

    Now the Bad News
    1. This is not a cure, in it's current form. This drug has only been tested on honeymoon diabetics and only been found to extend the honeymoon duration. 
    2. I'm not sure how big the effect really is, in terms of how much it would improve the life of a type-1 diabetic [d3]. 
    However, right now we have nothing that effects the body's immune system to help a type-1 diabetic.  Nothing at all.  If this treatment gets approved, then we will have one thing.  And we must start somewhere, so I do think getting this approved and available is a big step forward no matter what it's limitations.

    Comparison with Other Results

    Dr. Faustman's BCG results showed spikes of  .004 to .005 nmols of C-peptide [d4], so the DiaPep277 results are about 200 times bigger an effect than her results [d5], although her results were in established type-1 diabetics, not honeymooners.

    Dr. Orban's Abatacept (Orencia) results showed improvements of 60% in C-peptide production, as compared to 23.4% seen in DiaPep277 [d5].  However, Abatacept was in a phase-II trial, so it was smaller, and farther away from approval for type-1 diabetes.  But it is already approved for use for another disease.

    Dr. Pescovitz's Rituximab results showed improvements of about 20% in C-peptide production as compare to 23.4% seen in DiaPep277 [d5].  However, Rituximab was in a phase-II trial, so it was smaller, and farther away from approval for type-1 diabetes.  But it is already approved for use for another disease.

    More Data; Future Results
    There were a couple of data points that I wish were in the press release, but aren't.  I'll certainly be looking for them in the published paper.  First, a comparison of A1c numbers in treated vs. untreated.  See [d2] for details of what I'd like to see.  Second, a time based comparison: if an untreated type-1 reaches the end of their honeymoon N months after diagnosis (on average), how many months will it take someone with this treatment to get to the end of their honeymoon?  Third, some details on safety.  It's great to say "well tolerated", but I'd like to see the details.

    In terms of future work: obviously, these guys need to complete their analysis of this trial, complete their second phase-III trial, and get marketing approval from the FDA and EMEA.  That's just to get it widely available in the market.

    In addition there are several expansion paths which I hope they will take now, but might need to wait until after the treatment get approval.  (Once a drug is approved for any use, it is a lot easier to run a trial for other uses.)  Interesting lines of research would include:
    1. Trying it on patients before they were diagnosed with type-1 diabetes.  Many believe that anything that works in honeymooners will work better in people who have not yet been diagnosed at all.  Even a few years ago, however, we could not find those "not yet diagnosed" people, so we could not design a trial around them.  Now however, thanks to the "natural history" trial run by TrialNet [r2], we can find people who have not yet been diagnosed, and recruit them for pre-diagnosis trials.  So running a trial on people more likely to be diagnosed in the future, but not yet diagnosed, is an obvious thing to do.
    2. Combining it with other drugs.  Testing multiple drugs is becoming a common technique when there is no one drug that is completely effective.  For this drug, there are two ways to attack the problem.  One is try a combination of drugs all aimed at extending the honeymoon.  See if all of them together can actually stop the beta cell destruction and permanently preserve the beta cell function which is present at diagnosis.  Another track is to combine this drug with another drug which grows beta cells. 
    3. Trying it on established type-1 diabetes.  Majority consensus is that stopping type-1 diabetes when in starts (during the honeymoon) is easier than stopping it later (once established).  However, I'm still in favor of trying a drug that works on honeymooners, on established type-1 diabetics as well, especially when the side effects are very small or nonexistent.  Especially researchers who believe that beta cells continue to grow back slowly throughout a person's life, they might be particularly interested in a drug that lowers the autoimmune attack, even if given late in life.  Also, to put it bluntly, at this point established type-1 diabetics have little to loose, and few good options to try.
    Press release:

    News coverage:

    Extra Discussion and References

    [d1] Researchers can not measure insulin directly, because that would just measure how much insulin was being injected.  Measuring C-peptide tells them how much insulin the body is producing itself.  C-peptide is the official (by FDA) marker for approval of drugs to help type-1 diabetes, so it is the right thing to look at for trials like this.

    [d2] My personal requirement, is that changing A1c numbers by 0.5 is interesting and worth looking at, but that changing them by 1 is important, and obviously good without any further discussion.  My understanding is that most diabetes researchers are happy with 0.5, and consider even smaller changes interesting.

    [d3] Primarily, I'm not sure how much improvement there would be in terms of fewer side effects, less dangerous lows, etc.  I think the most important point here is duration of effect.  If the effect is long lasting, then it is reasonable to assume fewer long term side effects, but I have not seen any duration information.  Separately, there is also some debate about the benefit of having a longer, stronger honeymoon.  Some people hold that this just makes it tougher to treat type-1 diabetes: easier to have hypoglycemic events and harder to control BG and A1c numbers.  From a cure point of view, however, generating more of your own insulin is clearly the path to a cure, so I consider a longer, stronger honeymoon to be a good thing.

    [d4] Different research report C-peptide results in different units.  Dr. Faustman reports [r1] her results in terms of pmols / liter, and a pmol is 1/1000th of an nmol, so 5 pmols is the same as .005 nmols / liter.  On the other hand, Dr. Pescovitz reports in pmol / milliliter (which happens to be the same as nmol / liter). 

    [d5] Because there are several different ways to measure C-peptide production, I don't think this is a direct "apples to apples" comparison.  However, it is the closest to a direct comparison that I can make.  C-peptides can be measured in response to a meal, or while fasting.  The exact mechanism of measurement can vary as well.

    [r3] How it works in NOD mice:
    [r4] How it works in BB rats:

    Thanks to Abush at CWD for posting the first news of this, including the English translation.

    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. 

    Thursday, November 10, 2011

    Results from Trucco's Phase-I Dendritic Trial

    This is another "is the glass half full or half empty" kind of result. 

    This experiment was started in 2007.  People who had type-1 diabetes for more than 5 years were treated by removing dentric cells, treating those cells, and then reinjecting them.  This was done 4 times (2 weeks apart).  About 10 people were treated, but there was no placebo group.  This study was a phase-I trial, very clearly aimed at safety, not effectiveness.  As far as I know, this is the first clinical trial aimed at type-1 diabetes, which used this basic method (of reinjecting a patient's specially treated dendric cells).  So there were new and unique safety issues to be tested.  Just recently a second study using this same basic technique has started which you can read about here:

    This is from the abstract:
    CONCLUSIONS Treatment with autologous dendritic cells, in a native state or directed ex vivo toward a tolerogenic immunosuppressive state, is safe and well tolerated. Dendritic cells up regulated the frequency of a potentially beneficial B220+ CD11c− B-cell population, at least in type 1 diabetes autoimmunity.
    My translation is is this:
    First, there were no safety issues.  The treatment's safety was good.
    Second, there were some effects (which they think are good) on a particular type of B-cell.
    Third, there were no other effects seen (so no changes in C-peptide levels, A1c, or T-cells, for example).

    What does this mean?

    The most important  results, is that the treatment is undoubtedly safe enough to continue into phase-II trials.  (In the presentation below there is a letter from the FDA saying that.)

    But after that, did it work?  Very hard to tell, but it did not work as measured in the obvious ways by raising C-peptide levels, for example, or lowering antibody levels. The researchers hope that the change in B cells is a good sign, but I'm not sure that it is.

    It is important to remember that B-cells and T-cells come in all different types.  So when these researchers say B220+ CD11c− B-cells they are referring to one type specifically.  They hope that more B-cells of that specific type are a good thing, but this trial alone does not show that is so. For comparison, the most talked-about type of B cell is called CD20.  T cells that are researched as part of type-1 research include CD4 and CD8 (and many more).  I know of no other clinical trials working with this type of B-cell.

    Clinical Trial Record:

    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. 
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    Tuesday, November 1, 2011

    The Future Cost of Type-1 Cures

    Every now and then, someone will ask me how much I think a cure will cost, or they will complain that a cure that I take seriously will be too expensive (whatever that means), even if successful.  I have three thoughts that I always try to keep in my head when people talk about the cost of a cure:

    First, it is a total waste of time, to discuss the cost of something that you can not buy.  No one really knows how much something will cost, if they can not sell it, and you can not buy it.  It's like discussing ghosts or fantasy football.

    Second, "demand creates it's own supply" which is an economics phrase, that basically means that if people want something badly enough, then other people will find a way to make those things cheaper, which will change the basic economics of availability.  An example has to do with transplanting beta cells recovered from cadavers.  Right now, that doesn't result in a cure.  Some people say that could never result in a general cure, because there are not enough donated cadaver pancreases.  So such a cure is impossible, because even if it worked scientifically, there would not be enough cadaver pancreases.  But I don't agree with that logic.   For one thing, if cadaver pancreases could be used to cure type-1 diabetes, there would be a huge increase donated pancreases.  Groups like ADA and JDRF would launch public relations campaigns.  There would be scores of "feel good" local news articles about people cured with donated pancreases.   Suddenly, there would be many more pancreases donated.  At a minimum, every grandparent of a type-1 diabetic would be signing those forms. Furthermore, I would expect the technology to improve over time.  So if the first cure takes beta cells from three pancreases to cure one person, over time, it might take 2.5 and then 2, and maybe eventually 1.5 or even just 1.  That means that even thought the number of pancreases doesn't change, how many people they cure would change.  These are two examples of how "demand can create it's own supply".

    Third, technology makes everything (high tech) cheaper.  Computers that cost over $100,000 dollars in 1970, cost $2000 in 1980, and so on. My daughter has a $400 iPad, which probably has a lot more computing power than an entire Apollo moon launch from the 1960s, and so on.  Many of the possible type-1 cures that people are afraid will be "too expensive" are very high tech, and we can expect them to get cheaper over time as we learn how to build them, and the general level of technology improves.

    So my policy when thinking about cures myself, is not to worry about cost.  I know others do, and so I include that information when I have it.  But for myself: I only worry about availability, not cost.  Right now we have nothing.  So having a cure, even a really expensive cure, would be such a huge step forward, that I just can't bring myself to worry about the price.  I am sure that even if a cure starts out "too expensive" it will not stay that way for long. 

    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.
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    Thursday, October 27, 2011

    Atorvastatin (Lipitor), One down, one to go

    In the mid-2000s, two different groups started clinical trials which gave honeymoon type-1 diabetics Atorvastatin (Lipitor®).  One of these trials was at  Children's Hospital of Philadelphia (fondly known as "CHOP") and the other in Germany.  Lipitor is one of the most prescribed drugs in the world, and is used for long periods of time, so safety should not be an issue.  On the other hand, I could never understand exactly why anyone thought it would help cure type-1 diabetes.  Earlier this year, the German group posted their results.  Here is their conclusion:
    Atorvastatin [Lipitor] treatment did not significantly preserve beta cell function although there may have been a slower decline of beta-cell function which merits further study.
    Which I translate to "It didn't work."

    The CHOP study is a little overdue as well.  They were expected to finish collecting data in July 2010, so they've had about 15+ months to publish, but have not as yet.   Since that is the last Lipitor clinical trial that I know of, when we get the results from it, Lipitor is done.
    My Previous Blogging:
    Clinical Trial Record:
    Clinical Trial Record:

    A Little Discussion: What was the FDA's Orphan Products group thinking?

    One question you might have is do researchers think it would work?  After all, Lipitor is aimed a lowering cholesterol, which doesn't have any obvious connection to type-1 diabetes.  The basic answer is two fold.  First Lipitor is a immune modulator, so it might stop the immune system's attack on self.   Also, studies have shown that atorvastatin (Lipitor), and other statins, preserve beta cell function in a mouse model of type 1 diabetes.  But other studies have show that it did not work on NOD mice specifically.  So it was a known immune modulator, with conflicting results in animals.

    But it has two things going for it, separate from the question of "does it work".  First, it is known safe and widely used.  So that makes it very easy to work with and get approvals for.  The second thing is that it has a big company behind it.  (And for that company, it's a big deal drug.)  So they have a strong interest in finding new markets to sell it to, especially if they can somehow get patent coverage over a new use.  Anyway, that was good enough to get two clinical trials started.

    But there was one humorous note about this research:  The funders of the two trials.  The first trial was funded by Pfizer, which is just as you would expect.  They are the big pharma company that makes the drug.  But the second trial was funded by the FDA's Office of Orphan Products Development.  So here you have the biggest selling drug, from a huge drug company, and research is being funded by the office of orphan productions.  Both groups are funding research at about the same time, while the drug was still under patent.   It makes no sense to me.

    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.
    To Get as Email Join here:

    Sunday, October 16, 2011

    Two Summaries of Clinical Trials Aimed at Curing Type-1 Diabetes

    I keep two different summaries of the status of clinical trials aimed at curing type-1 diabetes, and I've just updated both of them.  So if you want a summary of the whole field, you might try looking at one or both of these:

    Summary Table
    This is a PDF file (so you can view it on the web), which is a table of all clinical trials aimed at curing type-1 diabetes.  From left to right it is organized by phase of clinical trial, so phase-I is on the left, and phase-III on the right.  Within each phase are three milestones: Has the trial started?  Is it fully enrolled? And have results been reported?  From top to bottom are different rows representing different techniques being tried to cure type-1.  So there is a row for immunology, a row for encapsulation, a row for inflammation, etc.

    This table contains one entry for each treatment which is currently being tested, and is designed to be printed out in black and white on a 3 foot by 4 foot poster.  It is very plain, with no graphics at all.

    This file is stored on, but anyone should be able to see it, here:
    or look here:
    for the whole directory of material. 

    Next Expected Milestone
    This is a list of all clinical trials currently or recently running aimed at curing type-1 diabetes.  My goal with this page is to make it easy, for each clinical trial, to see what research milestones are expected to be completed and when.   It can also serve as an TLOD ("too long over due") list of research that isn't reporting the expected results.  It also contains the last milestone that a trial reached, so you can see where everyone last was.

    This list contains one entry for each clinical trial which is currently underway, or recently was underway.  If many trials are being run on the same treatment, then there will be several entries in this list.  It is designed to be viewed on a computer monitor, so color is important.

    This file is part of my blog, and you can see it here:

    I update these files at least once a year.  (I try to do it once a quarter.)  If you see a mistake or something is missing, please tell me.  Thanks.

    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.
    To Get as Email Join here:

    Saturday, October 8, 2011

    Antibiotics and Type-1 Diabetes

    I occasionally get asked about a link between antibiotics and type-1 diabetes.  Basically, people want to know if our expanding use of antibiotics is causing cases of type-1 diabetes.

    The following study looked at this issue specifically (use of antibiotics causing type-1 diabetes) and found that it did not happen:

    Denmark has a centralized records medical system, so it is possible to do studies where you look at all children in the country, and compare their antibiotics usage to their type-1 diabetes status.  We could never do something like that here in the USA, but we can benefit from the studies done in other countries.  This study was based on about 600,000 patients, and was just published recently (in 2009).

    Here is about half of their abstract.  I've removed the numbers, so that it reads better:
    Use of any antibiotic was not associated with type 1 diabetes. Evaluation of type 1 diabetes risk according to number of courses of any antibiotic yielded no association between antibiotic use and type 1 diabetes. No specific class of antibiotics was associated with type 1 diabetes, no specific age of use was associated with type 1 diabetes, and no specific age at onset of type 1 diabetes was associated with antibiotics. In a large nationwide prospective study, no association between antibiotic use and type 1 diabetes was found among Danish children.
    I have not found any controlled clinical (human) studies which show that increased antibiotic use increases the chance of type-1 diabetes.

    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.

    Saturday, October 1, 2011

    JDRF Funding Research for a Cure 2011

    In the US, we are starting the "Walking Season" when JDRF asks us to walk to raise money for cure. So I'd like to do my part, by reminding you all how important JDRF is to the human trials of potential cures for type-1 diabetes, which I track. 

    Let me give you the punch line up front: 59% of the treatments currently in human trials have been funded by JDRF. (And the number is 76% for the later phase trials) This is an strong impact; one that any non-profit should be proud of.

    As you read the list below, please remember that it is a list of possible treatments, not a list of trials. Some of the treatments below have several different trials on-going right now.  Also remember that I give an organization credit for funding a treatment if they funded it any any point in development; I don't limit it to the current trial.  For example, JDRF is not funding the current trials for DiaPep277, but they did fund much of the early research into it, which allowed it to grow into human trials.

    Cures in Phase-III Human Trials
    Summary: there is only one treatment in phase-III right now, and it has been funded by JDRF.
    • Andromedia's DiaPep227 
    This treatment has more than one study active right now.

    Cures in Phase-II Human Trials
    Summary: there are 16, and 12 of them have been funded by JDRF, either directly or indirectly through ITN. Here are the treatments that have been funded by JDRF:
    • Abatacept by Orban at Joslin Diabetes Center
    • Diabecell by Living Cell Technologies    (Established)
    • Diamyd's GAD65 and lansoprazole and sitagliptin
    • Exsulin (previously INGAP) by Exsulin    (Established)
    • Kineret / Anakinra by Mandrup-Poulsen at Steno Diabetes Center
    • Liraglutide at Hvidovre University Hospital   (Established)
    • PROCHYMAL by Osiris Therapeutics
    • Rituximab by Pescovitz at Indiana
    • Sitagliptin and Lansoprazole at Sanford Health
    • Thymoglobulin (also known as ATG) by Gitelman
    • Umbilical Cord Blood Infusion by Haller at University of Florida
    • Xoma 52 by Xoma Corp  (Established)
    Not funded by JDRF:
    • Atorvastatin (Lipitor) by Willi at Children's Hospital of Philadelphia
    • Brod at University of Texas-Health Science Center
    • Canakinumab by TrialNet
    • NI-0401 by NovImmune

    Cures in Phase-I Human Trials
    Summary: there are 20, and 11 of the are funded by JDRF and 9 are not. Here is the list funded by JDRF:
    • Alefacept by TrialNet
    • AAT or Alpha-1 antitrypsin by OmniBio and also Kamada
    • ATG and GCSF by Haller at University of Florida    (Established)
    • BHT 3021 by Bayhill Theraputics   (Established)
    • CGSF by Haller at University of Florida
    • Trucco at Children’s Hospital of Pittsburgh    (Established)
    • IBC-VS01 by Orban at Joslin Diabetes Center
    • Leptin by Garg at University of Texas
    • Polyclonal Tregs 
    • Proleukin and Rapamune by Greenbaum at Benaroya Research Institute    (Established)
    • Lisofylline by DiaKine
    Not funded by JDRF:
    • ATG and autotransplant by Burt at University of Sao Paulo
    • BCG by Faustman at MGH (Established)
    • CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona  (Established)
    • Encapsulated Islets at University clinical Hospital Saint-Luc    (Established)
    • Etanercept (ENBREL) by Quattrin at University at Buffalo School of Medicine
    • Monolayer Cellular Device (Established)
    • Rilonacept by White at University of Texas
    • The Sydney Project, Encapsulated Stem Cells (Established) 
    • Pioglitazone by Wilson at Stony Brook 
    This summary does not include Artificial Pancreas research or stem cell trials, which I discuss separately.  The list above is a list of treatments, not a list of trials.  For example, the "ATG and autotransplant" treatment is actually running two trials (that I know of) one by Burt and another by Snarski, but since they are testing the same treatment, it is only one item in the list.  DiaPep277 is running several trials, Rituximab has two, and so on.  Each treatment gets one entry in the list, not each trial.  Finally, those treatments marked "(Established)" have at least one trial which is open to people who have had type-1 diabetes for over a year.  So those are open to non-honeymoon diabetics.

    Summary of all Trials
    37 in total
    22 funded by JDRF
    So 59% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

    Just Looking at Trials on Established Type-1 Diabetics
    13 in total (35% of all trials)
    8 funded by JDRF (61%)
    So 61% of the trials recruiting established type-1 diabetics, are funded by JDRF.

    Compared to Last Year
    In 2010 there were 33 treatments in clinical trials, in 2011 there are 37 (growth of 12%)
    In 2010 there were 4 treatments in Phase-III trials, in 2011 there is 1 (major drop: -75%).
    In 2010 there were 16 treatments in Phase-II trials, in 2011 there are still 16 (no change).
    In 2010 there were 13 treatments in Phase-I trials, in 2010 there are 20 (big growth: 54%).

    The big change this year is that 3 out of 4 phase-III trials have ended in failure.  That big, bad news.  The other side of the coin is that there are 7 new phase-I trials, but it's still a loosing trade off. The basic trade off is that -- on average -- starting 4.5 phase-I trials will eventually result in 1 phase-III trial.  So we gained the equivalent of about 1.5 phase-III studies, but lost 3. 

    The following two drugs might turn out to be treatments rather that cures, but right now it's not know how they will turn out, so I'm still tracking them as possible cures:
    • Liraglutide at Hvidovre University Hospital
    • Sitagliptin and Lansoprazole at Sanford Health 
    And finally, the Sitagliptin-only trial which I was covering as a possible cure last year, I now think is a treatment, so I'm removing it from the list of possible cures.
      How I Count Trials for This Comparison
      • I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle.
      • I mark the start of a research trial when the researchers start recruiting patients (and if there is any uncertainty, when the first patient is dosed).  Some researchers talk about starting a trial when they submit the paper work, which is usually months earlier.
      • For trials which use combinations of two or more different treatments, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug.
      • The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding.
      • I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway.
      • Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details.
      • I use the term "US Gov" for all the different branches and organizations within the United States of America's federal govenment (so includes NIDDK, NIAID, NICHD, etc.)
      • I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I'm an adviser to JDCA. I also own stock in several of the companies discussed here.
      This is an update and extension to blog postings that I've made for the last three years:

      Please think of this posting as being my personal  "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:
      Thank You!

      Finally, if you see any mistakes or oversights in this posting, please tell me!  There is a lot of information packed into this small posting, and I've made mistakes in the past.

      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.
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      Friday, September 16, 2011

      Stem Cell Research Checklist (and recent uterine stem cell news)

      Whenever I see stem cell research published, I always ask myself the following questions, in order to evaluate it's importance:
      • What animal was used in the research?
        • Humans are the best animals to use, obviously.
        • NOD mice, and other animals that have autoimmune diabetes are good to use.
        • Animals that have artificially produced diabetes are not so good.
        • Animals that don't have diabetes at all are the least promising.
      • Were the cells created true beta cells?
        • Sometimes people announce that they create "precursor" cells, or some other cell on the way to a beta cell, but not there yet.  
        • Making a complete beta cell is good, but not enough.
        • The best result, is making a beta cell that generates insulin in response to sugar in the blood.  That's what a real beta cell does.
      • What sort of immune suppression (if any) was used.
        • Any stem cell from another person (adult or embryonic) may trigger an immune response, so the first question is did they use the animal's own stem cells?
        • What sort of drugs, treatments, or encapsulations were used to prevent rejection of the stem cells?
      • Did it work in actual animals?
        • Some research just measure what the cells do in petri dishes or cell cultures, but the true measure of a beta cell, is what it does in a real animal that needs insulin.
        • Did the researchers measure C-peptides?
        • Did they need less insulin, see lower A1c and lower BG (especially after meals)?
        • The best would be no need for external insulin, and no bad side effects
      • How long did it work?
        • Obviously, longer is better (and remember to scale based on the lifespan of the animal involved).
        • It's always better if the experiment ended before the effect ended, rather than the other way around.
      • What's the plan for preventing the autoimmune attack from destroying the new beta cells?
        • Many stem cell researchers have a "that's someone else's problem" attitude, which I don't think is a good one.
        • A few stem cell options come with an integrated solution to the autoimmune attack, and those are a lot more interesting to me.
      (As I look back over this list, I think most of it could be used for any research which claims to be curing type-1 diabetes.  First ask yourself: what animal?  And so on.) 

      Applying the Checklist to a recent headline:
      Uterine stem cells used to treat diabetes in mice

      A press release is here:

      Here are the first few paragraphs (we've all read this stuff many times before):
      Researchers funded by the National Institutes of Health have converted stem cells from the human endometrium into insulin-producing cells and transplanted them into mice to control the animals' diabetes.
      The endometrium, or uterine lining, is a source of adult stem cells. Normally, these cells generate uterine tissue each month as part of the menstrual cycle. Like other stem cells, however, they can divide to form other kinds of cells.

      The study's findings suggest the possibility that endometrial stem cells could be used to develop insulin-producing islet cells. These islet cells could then be used to advance the study of islet cells transplantation as a treatment for people with diabetes. If the transplantation of islet cells derived from endometrial cells is perfected, the study authors write that women with diabetes could provide their own endometrial tissue for such a transplant, sidestepping the chance of rejection posed by tissue from another person. Endometrial stem cells are readily available and can be collected easily during a simple outpatient procedure. Endometrial tissue could also be collected after hysterectomy, the surgical removal of the uterus.

      How do I apply my checklist/questionnaire to that research?   Like this:

      What animal was used in the research?
      Two quotes from the abstract: "mice having a laboratory-induced form of diabetes" and "mice had few working beta cells. But the paper and in email from the author, things were a little more explicit: SCID mice were used, and their diabetes was triggered by giving them SZ toxin, which kills their beta cells.  SCID are "Severe Combined ImmunoDeficiency" mice.  These mice did not have autoimmune diabetes.  This creates some complexities, which I discuss below.

      Were the cells created true beta cells?
      Two quotes from the abstract: "The researchers found that some of these cells also produced insulin." and "the researchers exposed the mature stem cells to glucose and found that, like typical beta cells, the cultured cells responded by producing insulin." And the paper makes it crystal clear that the new beta cells did generate insulin in response to BG, and worked the way real beta cells are supposed to work.

      What sort of immune suppression (if any) was used?
      Nothing is mentioned in the abstract or paper.  SCID mice were used and they don't have a fully functioning immune system anyway.  In email, Dr. Taylor (lead author) said that he expects that a biopsy from one person would create enough stem cells to treat one person.  Discussion below about why that is important in terms of immune suppression, or lack of it.

      Did it work in actual animals? 
      Pretty well, but not perfectly.  The paper says that the mice had BG levels between 250-300, and were not given insulin.  This stayed pretty constant (my eye-balling of the data) during the weeks that the mice were followed. Obviously, the current standard of care is closer to 140, but remember that until the 1980s, BG levels around 300-400 were pretty standard.  So in this very first mouse experiment, they achieved better standard of care than the first 70+ years of human treatment.  And I expect they can refine their procedures to do much better.

      How long did it work?
      The abstract says "the animals continued to produce some insulin for six weeks, until the researchers ended the study." And the paper has more details on this.  The fact that they ended the study before the effect ended is promising as well.  It suggests that the effect will last longer.

      What's the plan for preventing the autoimmune attack from destroying the new beta cells?
      So far, there isn't one.  Since the mice in the experiment did not have autoimmune diabetes, the researchers didn't learn anything about what a type-1 diabetic's immune system would do to the new beta cells.  (Type-2 diabetics would not have this problem, of course.)  See below for some discussion about this.

      What does all this mean?

      My one sentence summary is: this is good research; very promising that it might be available in people in 15-20 years.

      I know that a lot of people are staring at their screens right now screaming silently "how can it be good research yet still so far from general availability? Good research should give me a cure, quickly!"  And the answer is that if it were not good research, it would be even farther away.  Just because we want a cure quickly, does not mean we are going to get it that quickly.  Human research takes 10-12 years to make it from start to general availability, so I'm assuming that this research starts human trials in 3-10 years.  Because this research was done in severely immune compromised mice, I would expect that they would need to do some experiments in NOD mice or similar before trying it in type-1 diabetic people.

      (Although the 10-12 year approval process is for drugs and devices, not surgical procedures, but this difference is too complex for me to describe here.  The much oversimplified version is: this research might take slightly less than the normal 10-12 years, but don't bet on it.)

      Why is this research good?
      Mostly because they made true beta cells that generated insulin in response to blood sugar and actually worked in real animals.  That's huge.  Even better, it continued to work for the length of the experiment.

      What about this research needs more work?
      It needs to run longer, for the whole life of the mouse.   It needs to be done on animals or people who have natural autoimmune diabetes.   Finally, it needs to be done in people.

      What about this research is complex?
      The type of mouse used combined with the lack of immunsuppression is the complex part of this research.  The mice used were SCID and these mice have seriously broken immune systems.  That's why they are used in transplant studies; they can't really reject foreign cells they way normal animal could.  So the researchers didn't have to give the mice an immunsuppresive drugs, because the mice were already immunsuppressed.  That all sounds pretty bad, in terms of applying this to people.

      But maybe not.  Dr. Taylor has told me that he is hopeful that a single biopsy would provide enough uterine stem cells to treat one person.   If so, perhaps a person's own uterine stem cells could be used to treat themselves.  In that case, no immunespressives would be needed, because it would not be a foreign transplant.  Finding doners would not be a problem, either.  At least not for female diabetics.

      The only issue remaining, and it is a big one, is this: would the body's own autoimmune attack kill of the new beta cells same as the old ones?  I would think they would.   However, the stem cell harvest / implanting process is simple (could be done in a clinic), so even if the new beta cells were attacked by the autoimmune process, maybe they could be replenished at every endo visit?  Or maybe every couple of endo visits?  That is why the researchers chose these particular stem cells to use: they are plentiful relatively easy to get, and are naturally replenished every month in women.

      I'd like to thank Dr. Hugh Taylor (lead author), for his information., and for giving me a copy of the paper.

      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.
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