Consensus Recommendations on Glucagon-like peptide-1 receptor agonists (GLP-1RAs) as adjunctive treatment for individuals with type 1 diabetes (T1D) using an automated insulin delivery (AID) system

Physiology of GLP-1RA Therapy in T1D

Strong Recommendations

  1. GLP-1RAs should be used in persons with T1D because they address several pathophysiological mechanisms without increasing the risk of hypoglycemia.
  2. People with T1D are unable to suppress glucagon during meals, which contributes to postprandial hyperglycemia, and this defect may be improved with GLP-1RA therapy.
  3. GLP-1RAs delay gastric emptying and might have GI-side effects, thus strategies to mitigate side effects (eating smaller portions, management of sickness/vomiting) should be discussed prior to initiation of treatment. This is particularly true for people with gastroparesis.
  4. Tachyphylaxis to the effects on gastric emptying may occur, but the magnitude of this effect as well as potential remedies are not well understood. 

Outcomes of GLP-1RA Therapy in T1D

Strong Recommendations

  1. GLP-1RAs can be beneficial in individuals with T1D to reduce the total daily insulin dose.
  2. GLP-1RAs can improve postprandial glycemic excursions in T1D.
  3. GLP-1RAs can improve HbA1c in T1D.
  4. Because GLP-1RAs have been shown to reduce postprandial peaks and mean glucose when used in conjunction with an AID system, there may be an opportunity to significantly improve glucose outcomes, as measured by a continuous glucose monitor, if AID systems and GLP-1RAs can be integrated in therapy.                                           

What is Lacking in AID Systems Therapy in T1D (Better Sensors)?

Strong Recommendation

Mild Recommendation

  1. GI side effects of GLP-1RAs can share symptoms with those of DKA. People using GLP-1RAs along with an AID system should be reminded that ketone monitoring for suspected DKA is standard of care independent of GLP-1RA use.
  1. Various ML algorithms with different levels of accuracy and computational load should be used with AID systems. Use of GLP-1RAs will create opportunities to develop new algorithms. 

What is Lacking in AID Systems Therapy in T1D (Better Algorithms)?

Strong Recommendations

Mild Recommendations

  1. Individualized titration of GLP-1RAs (e.g. lower dose and slow titration) for people with T1D using an AID system could be considered to minimize side effects, risk for hypoglycemia, and discontinuation.
  2. AID systems may provide a platform to safely test / initiate the use of GLP-1RA adjunct therapy in people with T1D.  Further investigations in the optimal adaptations of the mathematical algorithm for use with specific GLP-1RAs are needed.
  3. AID algorithms that automatically detect and dose for meal events may benefit from the delayed gastric emptying caused by GLP-1RAs such that
  1. AID systems need to automatically detect and modify insulin dosing in response to exercise, and glucose outcomes during exercise and GLP-1RA usage need to be studied.
  2. During uptitration of GLP-1RAs, AID system settings such as glucose targets, carbohydrate to insulin ratios, basal rate or correction factors depend on AID system functionality to minimize the risk of hypoglycemia.

 

What is Lacking in AID Systems Therapy in T1D (Better Insulin)?

Strong Recommendation

  1. GLP-1RAs might be useful if combined with faster acting insulin analogs for people with T1D who prefer to receive bolus doses immediately before a meal. The use of faster insulins in combination with GLP-1RAs also presents an opportunity to improve AID performance by potentially eliminating the need for meal announcements. However, since the GLP-1RAs delay gastric emptying, it would be necessary to study how the kinetics of faster mealtime insulins align with the delayed kinetics of carbohydrate absorption.

How will GLP-1RA Therapy as Adjuvant Therapy with AID systems Improve Performance in T1D and Which Patients are Most Likely to Benefit?

Strong Recommendations

  1. GLP-1RA based therapies should be considered as adjunctive therapy in specific populations of people with T1D, such as adults with overweight and obesity, insulin resistance, or higher insulin requirements, who are unable to achieve optimal glycemic outcomes.
  2. GLP-1RA based therapies should be considered in people with T1D using an AID system who experience postprandial hyperglycemia despite optimization of meal plans.
  3. Use of GLP-1RA based therapies could facilitate practical use of AID systems where severe insulin resistance is a barrier.
  4. Adjunct therapy might be particularly helpful for people at high risk for CVD/CKD or other existing comorbidities.
  5. Consider a diagnosis of T1D in the emerging frameworks of fair GLP-1RA allocation, especially if overweight or obesity are present.
  6. Reduction in insulin requirements could be seen in individuals with T1D using an AID system with adjunct GLP-1RA therapy, allowing those whose daily insulin needs exceed the capability of their AID system to deliver a necessary total daily insulin dose or a necessary bolus dose and to avoid the need for frequent refills of their reservoir.

What are the Knowledge Gaps, Controversies, and Recommendations for Research in the Use of GLP-1RAs as Adjuvant Therapy with AID Systems in T1D?

Strong Recommendations

  1. Manufacturers of weekly GLP-1RAs should test these products in people with T1D using AID systems. By doing so, the evidence base will be strengthened and regulatory approval can be sought if these agents prove to be safe and effective. 
  2. Future studies of GLP-1RA use by people with T1D using an AID system should address mitigation strategies for DKA and hypoglycemia.
  3. Phase 3 regulatory trials of GLP-1RAs are highly desired and encouraged for an adjunct indication in managing T1D. We call on pharmaceutical manufacturers of weekly GLP-1RAs to test these products in people with T1D using an AID system, so that these individuals may have an opportunity to use these drugs if the products prove to be safe and effective upon review by regulatory bodies. 

What Should Be the Role of GLP-1RAs with AID Systems in T1D?

Strong Recommendations

  1. Evaluation of GLP-1RA therapy for T1D users of AID systems should include assessment of which T1D patients benefit the most.
  2. An AID system can accommodate a reduction in insulin requirement induced by GLP-1RA therapy, thereby reducing the risk of hypoglycemia.           
  3. When using GLP-1RAs in people with T1D, clinicians should consider adjusting not only insulin doses but also other medications for comorbidities that are administered based on 1) body weight (e.g., levothyroxine for hypothyroidism) if weight loss occurs and 2) the person's underlying condition where their effects or side effects may be additive with those of the GLP-1RA.
  4. With availability of AID systems that enable achievement of glycemic goals, treatment focus in GLP-1RA users with T1D should also be on comorbidities, such as CVD and CKD.
  5. For AID systems to accommodate current formulations of GLP-1RA drugs, treatment would be a combination of manual (GLP-1RA therapy) and automated (AID) interventions.
  6. Given the independent benefits of GLP-1RAs, clinicians should consider complementing AID therapy in T1D with a GLP-1RA. Conversely, for people with T1D on GLP-1RA therapy, clinicians should consider switching from other insulin regimens to AID therapy.

Expert Panel

Halis Kaan Akturk, MD
Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Grazia Aleppo, MD
Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Lia Bally, MD, PhD
Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland

Eda Cengiz, MD, MHS
University of California San Francisco, San Francisco, CA, USA

Ali Cinar, PhD
Department of Chemical and Biological Engineering, Illinois Institute of Technology, Chicago, IL, USA

Kathleen Dungan, MD, MPH
Division of Endocrinology, Diabetes and Metabolism, The Ohio State University College of Medicine, Columbus, OH, USA

Chiara Fabris, PhD
Center for Diabetes Technology, University of Virginia, Charlottesville, VA, USA

Peter G. Jacobs, PhD
Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA

David C. Klonoff, MD, FACP, FRCP (Edin), Fellow AIMBE*
Diabetes Research Institute, Mills-Peninsula Medical Center, San Mateo, CA, USA

Rayhan A. Lal, MD
Division of Endocrinology, Department of Medicine, Stanford University, Stanford, CA, USA

Julia K. Mader, MD
Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria

Umesh Masharani, MB, BS
University of California San Francisco, San Francisco, CA, USA

Anne L. Peters, MD**
Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

Priya Prahalad, MD, PhD
Division of Endocrinology, Department of Pediatrics, Stanford University, Stanford, CA, USA

Signe Schmidt, MD, PhD
Steno Diabetes Center Copenhagen, Gentofte, Denmark

Viral N. Shah, MD*
Division of Endocrinology & Metabolism, Indiana University School of Medicine, Indianapolis, IN, USA

Jennifer L. Sherr, MD, PhD
Yale University, New Haven, CT, USA

Guillermo E. Umpierrez, MD, CDCES, FACE, MACP**
School of Medicine, Emory University, Atlanta, GA, USA

Eric Zijlstra, PhD
Profil, Neuss, Germany

*Chairs
**Assistant Chairs

The expert panel members met virtually three times on January 17, 2024, and April 24, 2024, and August 14, 2024.

This project was supported by grants from Novo Nordisk and Lifecare.