JDRF and ADA publish new staging system for early type 1 diabetes – September 24, 2015

JDRF and the American Diabetes Association (ADA) announced a new scientific staging system for early, presymptomatic type 1 diabetes today with the goal of enabling earlier diagnosis and more effective development of preventive therapies. The system, just published in the latest issue of Diabetes Care, divides the progression of the disease into three stages: (i) multiple islet autoantibodies with normoglycemia and no symptoms; (ii) multiple islet autoantibodies with dysglycemia (glucose intolerance) and no symptoms; and (iii) symptomatic type 1 diabetes. It is based on the concept, borne out by clinical studies, that the disease process in type 1 diabetes begins far before the onset of symptoms and that there is an early window of opportunity for intervention to prevent the development of full-blown disease. The specific proposal arose out of a very valuable workshop last October that included presentations from an impressive lineup of researchers on the progressive pathophysiology of type 1 diabetes and the need for better risk detection and more informative clinical trials for early-stage therapies. If widely adopted, this system could have significant implications for the clinical, commercial, and regulatory sectors. While JDRF Chief Scientific Officer Dr. Richard Insel stressed that this statement will not change routine clinical care in the near term, we are hopeful that it will create a more favorable climate for development of much-needed early interventions for prevention of type 1 diabetes, in particular. We are also curious what the implications of a similar paradigm would be for established type 1 diabetes or type 2 diabetes. We certainly applaud JDRF and the ADA, along with collaborators including AACE, the Endocrine Society, the Helmsley Charitable Trust, and ISPAD, for their efforts on this front. We are optimistic that the endorsement from such respected organizations will give this statement a great deal of weight.

• Clinically, this system could potentially help identify at-risk patients earlier and smooth the transition to symptomatic type 1 diabetes – we also anticipate that a larger denominator will help all the professional and patient advocacy organizations. As the JDRF/ADA announcement notes, type 1 diabetes is typically not diagnosed until significant symptoms (excessive thirst, frequent urination, weight loss, fatigue) have developed, and one-third of cases are diagnosed after acute DKA. Under this system, patients at Stage 2 (who have almost a 100% risk of progressing to symptomatic diabetes) could begin insulin therapy earlier and reduce the risk of developing DKA, which would be most valuable for patients. Of course, this would require more widespread screening for type 1 diabetes in routine clinical practice, and there are legitimate questions about how broad a population should be screened and how feasible it would be to integrate screening into routine visits. In a conversation with us (see below), Dr. Insel stressed that this staging system is not yet ready for clinical practice but is meant to serve as a scientific statement. However, he argued that the future of type 1 diabetes is prevention of symptomatic disease, and this staging system provides a positive step in this direction. 
  
  • Dr. Insel highlighted the Fr1da Model Project Diabetes as a promising screening initiative with similar goals. The program, co-funded by JDRF and launched this year in Bavaria, Germany, will screen for islet autoantibodies in children at well-child visits at three and four years of age, and has the potential to decrease the risk of developing DKA at diagnosis and preserve residual beta cell function.
• The most valuable effects of this system will likely relate to the drug development paradigm for novel early-stage therapies. Using progression from one stage to another as an endpoint in clinical trials (rather than waiting for the onset of symptoms) would, in our view, enable more efficient studies and create more incentives for companies to focus on patients at an earlier stage in the disease. Indeed, JDRF Chief Mission Officer Dr. Aaron Kowalski highlighted these efforts in recent talks at Friends for Life and AADE as an excellent way to make it more feasible for companies to conduct prevention trials. The system should also enable better risk/benefit assessments for specific therapies, both by clarifying the risk of doing nothing (which could be quantified as the risk of progression to the next stage) and allowing different therapies to be targeted to patients at specific stages.

Questions and Answers

Q: How does this staging system affect the number of estimated people with type 1 diabetes? How many children and adults would be estimated at each stage?

Dr. Insel: In the short term, there will be no widespread universal childhood risk screening outside of the clinical research arena. This statement is a scientific statement, not a clinical statement that will alter standard of care. While we do not know the numbers of individuals with undiagnosed type 1 diabetes, it is likely a multiple of those presenting with symptomatic disease. Population-based screening will definitely increase the numbers of people with type 1 diabetes. There are studies such as the Fr1da study that are screening general population children for presymptomatic type 1 diabetes by screening for islet autoantibodies.  The TEDDY study initially screened general population children and children with a first-degree relative with type 1 diabetes for HLA genetic risk and then followed the at-risk cohort for development of islet autoantibodies.

Q: So as we understand it, this would not change the number of people considered to have type 1 but it would help solidify those at high and medium risk of getting type 1?

Dr. Insel: If risk screening ultimately becomes the standard of care, then more individuals with presymptomatic type 1 diabetes will be detected.

Q: At what point do you see this becoming a clinical statement?

Dr. Insel: When we have available interventions that can delay progression to symptomatic type 1 diabetes or Stage 3.

Q: How well understood is the risk of progression at each stage?

Dr. Insel: Because all patients are different, the rate of progression is variable. We need to have better defined biomarkers to both better define further stages and better predict rate of progression from one stage to the next.

Q: Which stage is the most promising target for intervention?

Dr. Insel: Interventions are being targeted today to both Stage 1 and Stage 2.

Q: Can you say more about that? Do you mean beta cell regeneration? Anti-CD3? Other areas? What is most exciting?

Dr. Insel: TrialNet's abatacept prevention trial is enrolling in Stage 1. TrialNet's anti-CD3 trial is enrolling subjects in Stage 2.

Q: Will the FDA fully embrace this staging system? How much regulatory input was involved in its development?

Dr. Insel: The FDA did attend a workshop to develop the classification system. They want to be involved early on when discussing biomarkers and clinical trial design.

Q: Will the system lead to more widespread screening for type 1 diabetes in routine clinical care? If so, for how broad a population (first-degree relatives, second-degree relatives, all children, etc.?)

Dr. Insel: This approach is not ready for routine clinical care but is being applied to clinical research. There are several opportunities to screen in the field. We know that screening relatives only gets you so far. We need to do more screening and staging from the general childhood population. We must have cohorts who can enroll in clinical intervention trials to develop approaches to prevent symptomatic disease.

Q: Are there differences in how this system should be applied to children vs. adults?

Dr. Insel: We know that the rate of progression in children may be faster than in adults and there can be variation in rate of progression in different age groups.

Q: Are there correspondingly different rates in how complications advance in people with type 1?

Dr. Insel: The question is not relevant for the topic. The focus is on presymptomatic type 1 diabetes.

Q: Would a similar staging system be useful after the onset of symptoms (e.g., honeymoon phase, insulin dependence but no complications, onset of complications, onset of microvascular complications, onset of macrovascular complications)?

Dr. Insel: Right now we are just focusing this classification system on presymptomatic individuals. I think that what we are going to see is a precision-based approach in all diseases including established type 1 diabetes. But we are not there yet, and will need more biomarkers including imaging approaches.

Q: Could a similar paradigm be applied to type 2 diabetes - in other words, dividing up the many people with “pre-diabetes” and dividing those into higher and lower risk groups?

Dr. Insel: We already have this when you look at pre-type 2 diabetes. We will likely see new biomarkers that better predict progression to type 2 diabetes.

Q: How will this change impact fundraising and advocacy work in type 1?

Dr. Insel: Long term, the only potential cost-saving measure is prevention of disease. We must prevent symptomatic disease to see huge cost savings. We need to continue to prioritize prevention of type 1 diabetes.

-- by Emily Regier, Sarah Odeh, and Kelly Close