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Immune intervention for type 1 diabetes could be headed to clinical practice


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5 minutes

Jay S. Skyler, MD, MACP, FRCP
Jay S. Skyler, MD, MACP, FRCP

Until recently, attempts at creating a disease-modifying immunotherapy  for type 1 diabetes produced negative results or transient success, said Jay S. Skyler, MD, MACP, FRCP, moderator of the Scientific Sessions symposium Implementing Type 1 Diabetes Immune Intervention in Clinical Practice. Then in 2019, a study from Type 1 Diabetes TrialNet showed that teplizumab could delay development of clinical (stage 3) type 1 diabetes in individuals at stage 2.

Dr. Skyler, Professor of Medicine, Pediatrics, and Psychology, University of Miami Leonard M. Miller School of Medicine, and Deputy Director for Clinical Research and Academic Programs, Diabetes Research Institute, University of Miami, called teplizumab an “exciting prospect” that may become the first immune intervention approved for type 1 diabetes.

Stephen E. Gitelman, MD, said ongoing TrialNet studies are examining the efficacy of two additional agents for the prevention of type 1 diabetes: CTLA4 Ig (abatacept), a T cell co-stimulatory blocker, and hydroxychloroquine.

Stephen E. Gitelman, MD
Stephen E. Gitelman, MD

Dr. Gitelman, Professor of Pediatrics, Director of the Pediatric Diabetes Program, and the Mary B. Olney, MD/KAK Distinguished Chair in Pediatric Diabetes and Clinical Research, University of California, San Francisco, School of Medicine, offered a word of caution about the use of immune interventions in type 1 diabetes.

“When patients and families approach you about receiving an immune intervention outside of clinical trials, my suggestion is just say no,” he said. “I don’t think we’re at the point of doing this quite yet.”

Despite the introduction of new insulin analogs and devices like insulin pumps and continuous glucose monitors, and improvements in the prevention and screening for type 1 diabetes, no age group is consistently meeting glycemic control targets set by the ADA, as evidenced by data from the Type 1 Diabetes Exchange, Dr. Gitelman noted.

Immunologist Ezio Bonifacio, PhD, Director, Center for Regenerative Therapies, Technische Universität Dresden, Germany, discussed the role of genetic screening in type 1 diabetes immune intervention. Screening can be used to select participants for natural history studies and primary prevention trials, to prescreen for subsequent antibody testing, to identify antibody positivity with faster progression rates, and to personalize therapies, he said.

Ezio Bonifacio, PhD
Ezio Bonifacio, PhD

Children who have a first-degree family history of type 1 diabetes have about a 6% risk of developing type 1 diabetes starting at birth and decreasing with age. By comparison, newborns without a first-degree family history have a risk of about 0.4% for developing the disease. This risk also decreases with age. Dr. Bonifacio said genetic screening could be used to help identify children from the latter group who have a risk profile closer to children in the former group.

The Environmental Determinants of Diabetes in the Young (TEDDY) study demonstrated the influence of the human leukocyte antigen (HLA) genotype on type 1 diabetes susceptibility, and further research has identified about 80 gene regions that confer susceptibility, he noted.

“It will be primary prevention that can be applied to a large number of the population that will really make an impact to the incident numbers of type 1 diabetes,” Dr. Bonifacio said.

An intervention with 20% efficacy that can be applied to all infants will prevent the same number of type 1 diabetes cases as an 80% effective treatment—if one existed—applied to 25% of future cases, Dr. Bonifacio noted.

Andrea Steck, MD
Andrea Steck, MD

Andrea Steck, MD, Associate Professor of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado, said antibody screening in conjunction with monitoring and education results in a significant reduction of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes. This screening is bolstered by standardization of islet antibody measurements through international workshops, such as the Diabetes Antibody Standardization Program and Islet Autoantibody Standardization Program, combined with accurate risk assessment and prediction for type 1 diabetes with new definitions of disease stages developed in 2015.

“There’s a high prevalence of pre-symptomatic type 1 diabetes in general population children,” she said. “Once two antibodies are persistently present, progression to type 1 diabetes seems inevitable.”

Stage 1 disease includes patients with multiple antibodies and normal glycemia. Progression to stage 2 is marked by antibodies and dysglycemia. Stage 3, also referred to as clinical or classical type 1 diabetes, indicates antibodies have met diagnostic criteria.

Darrell M. Wilson, MD
Darrell M. Wilson, MD

Darrell M. Wilson, MD, Professor of Pediatrics, Stanford University, discussed options for assessing glycemia. The oldest measure, urine glucose, still plays a role in the clinical diagnosis of many patients with type 1 diabetes, he said. A newer approach, continuous glucose monitoring (CGM), plays a significant role in the management of patients with diabetes, and sensors are an integral part of closed-loop insulin delivery systems, he added.

There is a compelling rationale for CGM use in new-onset and established type 1 diabetes studies. With many clinics starting CGM soon after diagnosis, Dr. Wilson noted that many study participants use the technology before study enrollment.

“CGM provides very granular glycemic data and complete collection of lows,” Dr. Wilson said. “This may well demonstrate clinical benefit, in addition to the data that we get from C-peptides stimulation.”

Because of their poor repeatability, oral glucose tolerance tests are not ideal for assessing glycemia, he said.

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