Sunday, June 5, 2016

Metformin Starts a Large Trial To Prevent Type-1 Diabetes

This blog describes a single large, complex trial called adAPT (Accelerator Prevention Trial).  The simple summary for this trial is: The researchers intend to recruit people who have a higher chance of getting type-1 diabetes (because they have a close relative with the disease) and then give some of those people Metformin (the common type-2 drug).  They will then see if the drug prevents or delays type-1 diabetes onset (by comparing the people who got the Metformin to those who did not).  The researchers hope to contact every family in Scotland impacted by type-1 diabetes, and will run the main part of the trial for 5 years.

However, this trial is based on a non-standard theory about the root cause of type-1 diabetes, plus it is complex.  Throughout this blog posting, I have put reference footnotes (such as [r1] and [r2]) at the bottom, along with extra discussion footnotes, which look like [d1] and [d2].

Why Metformin As Preventative?

To summarize: these researchers believe that type-1 diabetes is caused by three factors (called "accelerators") and that Metformin will protect the beta cells from at least one of these accelerators and therefore prevent or slow down type-1 diabetes.

The Accelerator Hypothesis

This trial is motivated by the "Accelerator Hypothesis" which is an alternate theory on the root cause of type-1 diabetes.  The standard theory holds that the immune system's mistaken attack on beta cells in the pancreas is the cause of type-1 diabetes [d1].   The Accelerator Hypothesis holds that both type-1 and type-2 diabetes are caused by the same three factors:
  1. Lower beta cell replacement rate (sometimes called "constitution")
  2. Modern environments which make higher demands on beta cells  (this might be more overweight people, an environmental toxin, etc.)  
  3. An immune system which aggressively attacks stressed beta cells.
The important difference between these theories is that in the standard theory, the autoimmune attack is the cause of type-1 diabetes, while in the Accelerator Hypothesis, the immune system's attack on beta cells under stress accelerates the problem, but does not cause it.

It also changes how we think about curing type-1 diabetes.  In the Accelerator Hypothesis, the immune system is triggered by stressed beta cells sending signals which the immune system responds to.  This response might be overly aggressive, but it is not fundamentally in error.  So changing the immune system is not going to cure type-1 diabetes (although it may change its progression somewhat).  This contrasts with the standard theory, where fixing the immune system will cure the disease.

Factor 3 above (the immune system) results in the different symptoms between what we call type-1 and type-2 diabetes.  If the immune system is highly aggressive, there is a faster and younger onset of diabetes, which we call type-1.  If the immune system reaction is smaller or nonexistent, then onset is slower and older, which we call type-2.

The Accelerator Hypothesis was first proposed about 15 years ago by Dr. Terence Wilkin, and it has evolved slightly over that time.  Some discussion of how the theory has changed is in [d2], and the original wording is in [d3].

According to this theory, all three accelerators impact everyone with diabetes, although different people will have different "mixes" of the accelerators.

Discussion

You might think this theory is just word games: if the main accelerator is factor 2 (insulin resistance, over demand (often caused by overweight), or environmental factors, then that's just a different name for type-2 diabetes.  If the main accelerator is factor 3 (the immune response) then that's just a name for type-1.  And no one has ever measured beta cell replacement rate (factor 1), anyway.

But it's not just name changes.  For one thing, the theory holds that slowing down any of the accelerators will slow down the diabetes, so if someone with a broken immune system was very thin, their diabetes would be delayed, and maybe even be more like type-2.

A digression on weight: I know what you are thinking.  You are thinking "my kid wasn't overweight when first diagnosed with type-1 diabetes".  Some of you were thinking "I wasn't overweight when I was diagnosed with type-1 diabetes".  This theory doesn't mesh with my experience either and that does bother me, even if theories are not disproven by personal experiences.  Supporters point to (at least) five studies which show that people diagnosed with type-1 diabetes have higher BMIs (a measure of over weight) than others.  The [r7] paper has references to these studies [d4].  I'm not going to get into the non-scientific aspects of this theory [d5].

Obviously, this theory is controversial [d6].  Diapedia (an on-line, curated diabetes encyclopedia) has a generally negative summary of this theory [r8] or you can read this negative editorial [r9].  You can compare those articles to the researcher's 2009 summary of supporting data [r7].  It's a classic scientific argument with both sides pointing at their data.

But the bottom line is that it doesn't matter who thinks this theory is correct or who thinks it is wrong. What matters is that the researchers have gotten the money and regulatory approval to actually test it.  ("One experiment is worth a thousand expert opinions" -- Robert H. Mathies.)  Arguing about the theory is a waste of time right now.  They are testing it, and the only thing that makes sense is to wait for the results from the trial, and see what they show. 

This theory is similar to the "Inflammation Theory" as a cause of type-1 diabetes [d7].

Trial Structure

This trial will start in early 2016, and is expected to publish final results in 2022.
Children between 5 and 16 will be screened, and can enroll if they have two or more autoantibodies.
They hope to enroll at least 90 people in the pilot phase, and more later.

The contact listed in the clinical trials registry is Pauline Armory: paulinearmory@nhs.net
And the trial manager is Ann Turner: ann.turner@dundee.ac.uk
The general contact email is: Info@adaptdiabetes.orgAnd much more information is available on their web site: http://adaptdiabetes.org/
The news coverage lists a large number of doctors working at many different clinics, so my guess is that if you are in Scotland or Northern England, you won't have to travel far to participate.

(Note: my description of this clinical trial is based on information from the trial's web page [r1], two clinical trial records [r4,r5] and several news reports [r2], and these sources do not all agree with each other. I'm doing the best that I can, to combine these sources, but it is possible that some of the information here is out of date.)

For those who are enrolled, during the first four months, blood glucose levels will be tested after a meal.  At this point, the researchers want to see that Metformin is successful in lowering those peak blood glucose levels.  This is their signal that Metformin is having the effect that they want to test.

After this, people will be followed for five years, with regular autoantibody tests.  The researchers hope to see less autoantibody progression.  Also, they want to see slower progression.  Ideally, they would like to see both of these things.  Since more autoantibodies are seen in people actually diagnosed with type-1 diabetes, fewer/slower autoantibodies would be a clear signal that the treatment is working.

Finally, these people will be followed to track how many are diagnosed with type-1 diabetes via the traditional symptoms (high BG, etc.)  The researchers hope that fewer treated patients will actually come down with type-1 diabetes as compared to the control group.

This trial will take a long time:  recruiting the people + four months + five years.  The researchers are aiming to finish in 2022.  The autoantibody data will be available sooner (although I don't know if it will be published early).  Of course, the screening data (peak BG after a meal) will be available much earlier, but I'm not sure that will be published and even if it is, I don't think (by itself) it's critical to a cure.

The trial is being funded by JDRF.

Extra Discussion

[d1]  This is called "autoimmunity" or "autoimmune attack" because the immune system is attacking the body's own cells, rather than foreign cells, as it should.

[d2] If you compare the more recent wording of the hypothesis to the original wording, you can see the following differences:
  • Recently, factors 2 and 3 are emphasised more while factor 1 is downplayed.
  • Earlier, weight gain was described as the primary cause of factor 2.  Later, this was changed to insulin resistance, and even more recently to environmental factors in general.
  • Earlier descriptions of the hypothesis focused on both types of diabetes as being "the same" disease.  Later descriptions focus on both types of diabetes have shared causes, but does not describe them as being the same disease.
The original 2001 definition is in the "extra discussion" section [d3] below.

[d3] Quoted from [r8] but originally from [r6], this is the original 2001 hypothesis:
The ‘Accelerator Hypothesis’ argues that Type 1 and Type 2 diabetes are one and the same, distinguished only by their rate of beta cell loss and the accelerators responsible. The first accelerator, a constitutionally (intrinsically) high rate of beta-cell apoptosis [cell death or cell "turnover"], is necessary for diabetes to develop but in itself rarely sufficient to cause it. Insulin resistance, the second accelerator, results from weight gain and physical inactivity which further increases the rate of beta-cell apoptosis and accounts for the rising incidence of Type 1 as well as Type 2 diabetes in industrially developed societies. Finally, a small and genetically defined subset of patients with both intrinsic lesion and insulin resistance develops beta-cell autoimmunity, the third accelerator.
[d4] As you can imagine, measuring BMI at type-1 diabetes at diagnosis is not a simple thing. Because weight loss is a classic sign of type-1, these researchers actually compared BMI at some point after diagnosis to a control group, but that is not perfect, either.  They were weighing people during the earliest phase of the honeymoon, and I'm not sure that really represents weight just before onset.  (Plus, the whole idea of "onset" is being reevaluated based on the TrialNet data.)

[d5] Many in the type-1 community have been complaining for years that media and many doctors do not differentiate between type-1 diabetes and type-2 diabetes, when they should.  This theory postulates that there is only one diabetes, and there really is no fundamental difference between type-1 and type-2.  Even worse, the type-1 community has argued for years that type-1 is not a "lifestyle disease" caused by being overweight, but this theory holds that it is (or at the very least, being overweight contributes to the disease).  So there are plenty of non-scientific reasons to hope this theory is wrong.

[d6] Indeed, one editor who published an update to the theory revealed that two of his peer reviewers had rejected the paper. However, the the editor was publishing it anyway, because he felt minority viewpoints should be aired publicly.  He accompanied the article with an opinion piece by the editor himself stating that he personally thought the theory was wrong.

[d7] The Inflammation Theory holds that beta cells become inflamed, and this inflammation triggers the autoimmune attack.  The Accelerator Hypothesis hold that beta cells are under metabolic stress which causes them to be attacked by the immune system (although this attack may be more or less aggressive).  I view "metabolic stress" and "inflammation" as related concepts, although not everyone does.

The Inflammation Theory was quite popular several years ago, and motivated several clinical trials. However, as of now, I think that only one of those inflammation based prevention treatments is still being tested. That is AAT.  

References and Sources

[r1] Trial Website: http://adaptdiabetes.org/
[r2] News Article: http://www.techtimes.com/articles/151904/20160420/new-trial-aims-to-prevent-type-1-diabetes-in-children.htm
[r3] Press Release: http://medicine.exeter.ac.uk/news/title_506628_en.html

[r4] EU Clinical Trial Registry:
https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-000748-41/GB
https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-000748-41
EudraCT Number: 2015-000748-41  (this is a European clinical trial registry number)
[r5] UK Clinical Trial Registry: https://www.ukctg.nihr.ac.uk/trials/trial-details/trial-details?trialId=34351
The UK trial registry lists this trial ID as 20540, but the query above uses 34351, and I don't know which one is correct.

[r6] Here is the original paper on the theory, from 2001:
http://download.springer.com/static/pdf/213/art%253A10.1007%252Fs001250100548.pdf?originUrl=http%3A%2F%2Flink.springer.com%2Farticle%2F10.1007%2Fs001250100548&token2=exp=1462141633~acl=%2Fstatic%2Fpdf%2F213%2Fart%25253A10.1007%25252Fs001250100548.pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Farticle%252F10.1007%252Fs001250100548*~hmac=2a7ec6140ae9ef099ca55256b1e12795f78cb39c2aa342820a7705fb547a038d

[r7] Much more detail on the Accelerator Hypothesis of type-1 diabetes in included the following 2009 review article, written by the same researcher who is running this trial:
http://www.nature.com/ijo/journal/v33/n7/full/ijo200997a.html

[r8] http://www.diapedia.org/type-1-diabetes-mellitus/21040851194/accelerator-hypothesis

[r9] http://link.springer.com/article/10.1007/s00125-007-0726-9/fulltext.html

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

3 comments:

Jeff said...

You are an amazing teacher.

Mark Winstanley said...

Really a nice meter of this post. I read your post. Thanks for share your post with us.

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Rick said...

I learned a great deal about Metformin, thanks.


I referred your blog to the TUDiabetes blog page for the week of June 13, 2016.