December 19, 2025

Leads:

Carol Levy – Mt. Sinai (Adult)

Emily Coppedge – Cornell (Peds

Participants: Viral Shah, Timothy Bol, Don Buckingham, Marissa Contento, Lauren Golden, Marina Basina, Sarah Dempsey, Arati Nagarkar, Amanda Perkins, Margaret Grillo, Erin Cobry, Abha Choudhary, Hailee Delsart, Lauren Waterman.

Meeting Agenda:

• Welcome
• Presentation by, Viral Shah, MD (Indiana University)
• Topic: Off-label Use of Adjunctive Therapies with Hybrid Closed Loop
• Discussion on current best practices recently implemented

Introduction

• Shah will focus on GLP-1 therapies but is open to discussing SGLT therapies as well.
• The presentation will cover:
  • Why are adjunct therapies needed.
  • Available options.
  • Best Practices.

Why Adjunct Therapies are Needed

• ADA standard of care acknowledges the availability of adjunct therapies.
• A1C target of less than 7% is not achieved by the majority of patients, even with AID (Automated Insulin Delivery) systems.
• Colorado study (2012-2021) examined A1C levels achieved with different technologies.
• Patients using CGM (Continuous Glucose Monitoring) but not AID: 44% achieved A1C less than 7%.
• Patients using AID: 51% achieved A1C less than 7% (7% improvement at the population level).
• AID systems are effective at nighttime, but daytime management remains challenging due to food, exercise, and other factors.
• Obesity prevalence is increasing in type 1 diabetes, mirroring the general population.
• The mean BMI in the T1D exchange is 27 (overweight).
• CVD (Cardiovascular Disease) mortality is high in type 1 diabetes.
• Swedish data shows a decrease in adjusted standardized incidence rate, but a significant difference remains compared to individuals without diabetes.
• Life expectancy for people with type 1 diabetes is about a decade less than the general population.
• Question raised about comparison of CVD death rates between type 1 and type 2 diabetes, and whether duration of diabetes was normalized in studies.

Adjunctive Therapies in Type 1 Diabetes

• Any therapy used in type 2 diabetes could theoretically be used in type 1 diabetes.
• A literature review of metformin and DPP4 inhibitors was conducted. At the time, there weren’t many studies on SGLT2 inhibitors.
• Metformin:
  • A1C and weight reduction were neutral.
  • Some studies showed improved insulin resistance and reduced surrogate cardiovascular measures.
  • No significant difference in carotid intima, media thickness, or pulse wave velocity compared to placebo.
• DPP4 Inhibitors:
  • Few studies, generally neutral in terms of glycemic efficacy.
  • No studies on surrogate cardiovascular outcomes in type 1 diabetes.

SGLT2 Inhibitors

• SGLT2 inhibitors have a bright future with continuous ketone monitoring (CKM).
• NIH and Abbott are funding studies to use CKM to mitigate DKA risk with SGLT2 inhibitors in type 1 diabetes.
• Studies are being conducted by Rich Birkenstall and Jennifer Scheer, among others.
• Studies have not started yet due to the current environment.

Issues with Liraglutide Trials

• There were issues with the liraglutide trials, including aggressive insulin dose reductions.
• Many sites had less experience, leading to potential issues with patient management.
• Some felt that people were too aggressively reducing the doses.
• Some sites did not have anyone flipping to DKA.

Adjunct 1 and 2 Studies Learnings

• The red highlights are corrected in allele surpassed T1, D1, and 2.
• CGM is essential for insulin titration, and AID is even better.
• Adjunctive therapy should be considered once patients are on an AID system for safety.
• GLP1 doses and insulin dose titration should be flexible.
• Adjunct 1 had forced titration, causing issues like severe GI problems and ketotic events.
• Frequent insulin dose adjustments are necessary, especially in the first six weeks.

Side Effects Analysis

• Lower BMI (less than 27), longer diabetes duration (more than 25 years), lower daily insulin dose, and undetectable C peptides were associated with higher adverse events and discontinuation.
• This is a post hoc analysis, and there’s no mechanistic explanation.
• Lower BMI may indicate a lower threshold for tolerating side effects for weight loss.
• Longer diabetes duration and lower C peptide levels may indicate underlying gastroparesis.

Semaglutide Trial Design

• Trial design considered factors from previous analyses.
• Inclusion criteria:
• Adults with type 1 diabetes for over a year.
• AID use for more than three months.
• A1C of 7-10%. BMI of 30 kg/m^2 or more.
• Multi-center, double-blind, placebo-controlled trial funded by Breakthrough T1D, with drugs provided by Novo Nordisk.
• Protocol was written before COVID and underwent six revisions with Novo Nordisk.
• Initial funding fell through due to legal requirements for multi-center studies.
• Novo Nordisk provided the drug after Breakthrough T1D provided funding.
• The trial used Ozempic at 1 mg per week because Wigovy wasn’t an option at the time.

Insulin Titration Recommendation

• Published an insulin titration recommendation similar to the algorithm used in the Semaglutide study.
• The recommendation is for Medtronic 670, 780 OmniPort 5, and Tandem Control IQ pumps.
• Titration should be based on baseline A1C:
  • A1C > 8%: Goal is to reduce A1C.
  • A1C 7-8%: Reduce insulin by about 20%.
  • A1C < 7%: Reduce insulin up to 30% or more for renal/cardiovascular benefits.
• Focus on key settings in AID systems:
  • Medtronic 7 AEG: Target 100 EIT of two.
  • Recommend updating weight in Tandem Control IQ if weight loss is more than 5-10%.
  • Islet: Recommend rebooting the system due to increased insulin sensitivity.

Primary Outcome

• The study used a composite primary outcome: time in range of more than 70%, time below range of less than 4%, and reduction of body weight of more than 5%.
• 36% in the semaglutide group achieved the primary outcome vs. 0% in the placebo group.
• The number needed to treat was three.
• A1C was similar between groups: 7.8% vs 7.7%.
• There was a 0.8% reduction in the semaglutide group and 0.5% in the placebo group, with an adjusted difference of 0.3.
• Shah notes an unexplained A1C drop in the placebo group between weeks 20-26.

Time in Range and Weight

• Significant improvement in time in range with semaglutide.
• Weight was approximately 9 kg lower in the semaglutide group at the end of the study, with no change in the placebo group.
• Glycemic effects of semaglutide are profound early on, with A1C stabilizing after a few weeks at 1 mg dose, while weight loss continues.
• One participant on placebo was convinced they were on semaglutide, requested 1mg prescription after the trial ended, and ended up in the hospital due to intolerance.

Insulin Dose Reduction

• A paper on insulin dose reduction has been accepted in diabetes care.
• The study aimed to determine how much of the reduction is due to weight loss versus the drug itself, using mediation analysis.
• 80% or higher reduction in insulin requirement is purely due to an effect of drug.
• Reduction in carbohydrate intake was only 30 grams per day.
• The assumption is that baseline data is consistent throughout the study period.

Insulin Titration Guidance

• Reducing insulin by 20-30% upfront when starting a GLP (2.5 mg tirzepatide or 0.25 mg semaglutide) is sufficient.
• GLP may have a secretary effect on beta cells, leading to a significant reduction in total insulin in the first four weeks.
• The effect at two weeks is almost the same as at four weeks in terms of insulin reduction.
• Planning to do a C-peptide analysis to assess changes over time.
• The data from the study will be made publicly available in a couple of months.

Semaglutide Use in Older Type 1 Patients

• Emily from Cornell has used semaglutide in older type 1 patients (16-18 years old) who were obese and poorly controlled.
• These patients were post-pubertal.
• Lauren Waterman from the BDC is doing work on this in adolescents and young adults.

Ongoing Studies

• Yale’s Jennifer Sherr’s group is doing a clamp study in young adults.
• Tennessee is combining semaglutide with teplizumab in stage 2 type 1 diabetes.
• It is not clear if they are doing a clamp.
• A UK study, in collaboration with SUNY Upstate New York, will use both SGLT2 and GLP1 together.
• Half of the recruitment will be in the UK, half in the US.
• This trial is funded by Breakthrough T1D.
• Lilly has clamp data on GIP only in type 1 diabetes, but it is not published.
• The SURPASS T1D 1 and 2 trials are ongoing for 52 weeks.
• The SURPASS T1D 1 26-week trial is doing MMTT in everyone at baseline.

Presentation: GLP-1RA in T1D_T1DX 2025

Recording: Hybrid Closed Loop Working Group-20251219_140308-Meeting Recording.mp4