Wednesday, June 22, 2016

Summary of ADA 2016

Every year the American Diabetes Association holds the largest diabetes conference of the year.  This year it was in New Orleans.  Attendance was over 16,000 people with 58% international participation. Although I did not attend, I did read (or at least skim) all the abstracts, and read all the tagged tweets that came out of the meeting.  This is my summary.  There were 100s of abstracts, scores of talks, and 1000s of tweets, so I'm only mentioning the most interesting items here.  I've divided this posting into four sections:

  • A very quick summary of the most important findings.
  • Coverage of clinical trials aimed at curing type-1 diabetes.
  • Coverage of research aimed at curing type-1 diabetes (but not yet in people).
  • Other items of interest.
A Very Quick Summary

The big type-1 news was all about artificial pancreas research.  The "Do It Yourself" artificial pancreas crew had a poster or two, plus a few meetings, but they dominated the buzz for the first day of the convention.  The commercial / professional artificial pancreas developers took over for the second day, with lots of published data.  

There was also more focus this year on "Quality of Life" issues.  Not just better numbers, but a better life.  More discussion of the whole person, and not just BGs and A1Cs.  Memorable quote was "The data alone can't be enough to make a decision", but I did not write down who said it.  There was also some discussion of using more patient friendly terminology (especially in the type-2 world).

In the world of type-2, the LEADER study showing several good outcomes from using liraglutide‎/Victoza and more data from EMPA-REG (both huge studies) made big news.  Everyone was talking about Metformin as though it was the next Vitamin-D (or the Vitamin-C of the 1970s...).

You'll notice I didn't mention much about clinical trials aimed at curing type-1 diabetes, or even curing type-1 at all.  There were two posters on clinical trials aimed at curing type-1 diabetes, and less than 10 talks aimed at curing type-1 diabetes, and that was about it.

This is DiabetesMine's summary of ADA 2016 (they cover a lot of topics which I do not):

Reports From Clinical Trials Aimed At Curing Type-1 Diabetes 

Combination Therapy with ATG + GCSF in Established Type 1 Diabetes: Two-Year Outcomes
Poster 1676-P:  
These researchers had previously reported beta cell preservation at 12 months.  (Meaning that most diabetics lost beta cells over time, but for those treated with ATG and GCSF their beta cell count remained constant.)  The result here is that after two years, treated and untreated people with type-1 diabetes had the same C-peptide numbers, so whatever advantage was seen after a year was not seen after two years.  (There were some immunological differences seen, but the C-peptide numbers, which are the most important in terms of a cure for type-1, were the same.)

Update on BCG Clinical Program for Reversal of Established Type 1 Diabetes

This is an update on Dr. Faustman's  phase-II study of BCG, which I've blogged on before.  The key new information is that they have recruited 125 patients out of the 150 people they need.  For one year of recruiting at one site, that is strong progress.  It suggests they will be fully enrolled by the end of the year.  Since the study runs for 5 years, we can expect completion in late 2021 and publication thereafter.  

Also, there is a single line on the poster about "Clinical Program 3" which is a new study.   It will give repeat doses of BCG to people who were already in the phase-I trial.  I think of it as a follow on study to the phase-I trial.  Since only three people got BCG in the phase-I trial, this clinical program will be tiny.

5-IT-SY03 - What Is the Future of Immunotherapy for Type 1 Diabetes?
This session contained about 5 talks which focused on using immunology to cure type-1 diabetes. Unfortunately, there were no abstracts for the talks, and no information about them at all.  So my only knowledge is a few tweets and web articles.
  1. Here is the official ADA preview of the session:
  2. There was general optimism about IL-2 (which I just recently blogged about).
  3. There was pessimism about antigen-based therapies (ie. blocking the immune system's reaction to a specific target):  "Antigen-based new onset and Immunomodulatory onset studies have really not showed any positive substantial results.  --Jay Skyler MD"
Safety and Tolerability Results from a Phase-I study of Phizer's PF-06342674
PF-06342674 is a antibody that blocks a part of the immune system (IL-7 binding). This trial is testing physical properties of the treatment (how much ends up in the body, how quickly the body sheds it, any adverse effects, etc.) This is called "safety and tolerability". This trial is not in any way testing that PF-06342674 will treat or cure type-1 diabetes, but based on what is learned here, future studies could test this as either a treatment or a cure.

Optimistic Overview of Transplanting Pig Islet Cells Into People
My comments: LCT is the company farthest along in transplanting pig islet cells.  They have done several phase-I and phase-II clinical trials, but the results have not led to a cure as yet.  As for islets from stem cells, Viacyte has started a phase-I trial.  Neither LCT nor Viacyte announced new data at ADA 2016 (that I know of).

Leptin (Metreleptin) In Patients With Type-1
We conclude that metreleptin was not efficacious in improving glycemic control in T1DM although it reduced body weight and daily insulin dose modestly.
My comments: In the past I have covered Leptin as a possible cure for type-1 diabetes.  However, this study suggests that, while it might lower insulin usage, it is not a cure.

Other Cure Research 
(I'm including a few AP papers here, but nowhere near all of them.)  From here down, this posting is mostly links to other sources of information.  Different people will be interested in different topics, so I encourage you to read the source material for the topics you care about.  My few comments are in italics.

Transplants  (But Still Need Lifetime Immunospressive Drugs)!/4008/presentation/44271
My comments: one patient, but successful.

873-P / 873 - Pilot Study of Tidepool’s Blip Application for Data Visualization in Type 1 Diabetes (T1D)!/4008/presentation/39609

AP Papers, Posters, Tweets, etc.

What do people think an AP is?  (It turns out to be totally different than what I think it is.)!/4008/presentation/39746

More commerical AP links:

DiabetesMine @DiabetesMine
In designing AP pivotal trials, discussion is to make them 6-12 months to pursuade payers. Beyond FDA's 3-month requirement. #2016ADA
My comment on this last tweet: The FDA has made it clear that they will approve APs based on 3 month clinical trials.  (I think this even covers bihormonal APs, which would include approving a lifetime of Glucagon micro doses with only 3 months of testing.)  However insurance companies may not pay for APs based on 3 months of data.  They might argue for more data to show it really is better.  Therefore there is pressure to run longer phase-III trials, so that one trial can lead to both FDA approval and insurance company payment.  But that would delay initial FDA approval while the longer trials completed.  There was a similar issue in CGMs.  They were approved by the FDA, but some insurance companies would not reimburse until the JDRF funded a longer study that showed benefits that the insurance companies could accept.

More "we are not waiting" (Homebrew AP) links:
While using #OpenAPS: self-reported outcome measures showed median HbA1c dropped from 7.1% (SD 0.8%) to 6.2% (SD 0.5%). #2016ADAWhile using #OpenAPS: self-reported outcome measures showed median HbA1c dropped from 7.1% (SD 0.8%) to 6.2% (SD 0.5%). #2016ADA
#OpenAPS self-reported outcome measures showed median percent time in range (80-180 mg/dL) increased 58% (SD 14%) to 81% (SD 8%). #2016ADA
Of note: user growth of #OpenAPS is doubling every 3 months, even though users must self-build these AP systems. #2016ADA
My comment: that is a growth curve that any high-tech start up would be proud of.

Other Interesting Research
There were vast amounts of "my new insulin is better than your existing insulin" research.  None of that is included here.  If you care about the new insulins, I would search the ADA material directly, or wait for the press release announcing it is for sale in your country.

Easing the Child to Young Adult Transition
Two good tweets from Dan Browne:
Monaghan: for young adults, shared responsibility w/ parents for t1d care correlates with worse hbA1C. #2016ADA @collegediabetes
#2016ADA Monaghan: protective factors for YA A1C: pers. responsibility, contact w providers, fear of hyperglyc. #2016ADA @collegediabetes
My comment: what this seems to say is that giving young adults personal responsibility for their BG is a better strategy than shared responsibility.  I don't think that is conventional wisdom, however.  I do think this talk will be available on line in the future, and will be worth viewing when it is.

Systematic Population Screening, Using Biomarkers and Genetic Testing, Identifies 2.5% of the U.K. Pediatric Diabetes Population With Monogenic Diabetes.
via Eleen Ullman's tweet:

CGMs Beat Diabetic Alert Dogs 
Basically, CGMs detected lows earlier than dogs, and dogs often alerted when there was not a low situation.  You can read more in this news article:
And three tweets on that talk:

Causes of Death for People With Type-1!/4008/presentation/40218
1473-P / 1473 - Causes of Death in the First 100 Type 1 Diabetes (T1D) Donors in the Network for Pancreatic Organ Donors with Diabetes (nPOD)
My comment: the link above goes to an abstract.  It is tough to read but important.  Deaths directly caused by type-1 were very common.  So was suicide and drug use.  This is very cautionary data which should not be ignored.

Inhaled Insulin
MannKind announces more data (six posters) on their inhaled insulin: 

Dosing For Protein
Pratik Choudhary tweeted:
#2016ADA - preliminary results show 60 gms protein require 25% more insulin - practically - % increase of bolus with increased fat or prot

Nasal Glucagon

Type-1 Diabetes and Autism!/4008/presentation/40873!/4008/presentation/40901

Type-1 Diabetes and Sleep Apnea!/4008/presentation/39594

Metformin (there was far more than this)!/4008/presentation/39832

Shaming Is Common:
LEADER data:
My comments: If you have type-2, you may want to discuss this with your doctor.  (And even if you don't, your doctor may want to discuss it with you. :-)
EMPA-REG data:
Position paper on terminology for "Diabetes"
My comments: This statement misses what I consider the two most important rules:
Differentiate between type-1 and type-2 diabetes! (when appropriate)
Do not say "diabetes" when you mean "type-2 diabetes" or when you mean "type-1 diabetes".

More Interesting Tweets:

Doctor Deena @Doctor_Deena
Amazing #technology for #diabetes-- a skin patch using wavelengths to deliver #insulin into skin pores. #2016ada

Mark Harmel MPH, CDE @MarkHarmel
Results of DiaMonD study (CGM in MDI users) impressive. #2016ADA Fewer highs, lows and reduced variability. + Lower A1C by 0.9% at 24 weeks
My comment: MDI is multiple daily injections.  What this study is showing is that even people who are not using a pump will benefit from using a CGM.  While I suspect this is true, I'm not sure it is useful, because I suspect these people don't want or cannot use a CGM for the same reason they don't want or cannot use a pump: they don't want an attachment or can not afford it.  Telling non-users "it is good for you" will not make them users: they know it is good for them.  They have other reasons for not using it.

Dr.Harsha Doddihal @Harshadod
Consuming #proteins followed by carbs could be beneficial in #glycemic control! Poster 62-LB
My comment: is this news?  I always thought eating carbs after non-carbs led to smaller post meal BG spikes.

Joshua Levy
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.

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.


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:
And the trial manager is Ann Turner:
The general contact email is: Info@adaptdiabetes.orgAnd much more information is available on their web site:
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:
[r2] News Article:
[r3] Press Release:

[r4] EU Clinical Trial Registry:
EudraCT Number: 2015-000748-41  (this is a European clinical trial registry number)
[r5] UK Clinical Trial Registry:
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:*~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:



Joshua Levy
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.