Combination SGLT2 Inhibitor and Glucagon Receptor Antagonist Therapy in Type 1 Diabetes: A Randomized Clinical Trial
Open accessAbstract
OBJECTIVE: To examine the effects of insulin-adjunctive therapy with a sodium–glucose cotransporter 2 (SGLT2) inhibitor and a glucagon receptor antagonist (GRA) on glycemia, insulin use, and ketogenesis during insulinopenia in type 1 diabetes. RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled, crossover trial we assessed the effects of adjunctive SGLT2 inhibitor therapy (dapagliflozin 10 mg daily) alone and in combination with the GRA volagidemab (70 mg weekly) in 12 adults with type 1 diabetes. Continuous glucose monitoring, insulin dosing, and insulin withdrawal tests (IWT) for measurement of glucose and ketogenesis during insulinopenia were completed during insulin-only (Baseline), SGLT2 inhibitor, and combination (SGLT2 inhibitor + GRA) therapy periods. RESULTS: Average glucose and percent time with glucose in range (70–180 mg/dL) improved with combination therapy versus Baseline and SGLT2 inhibitor (131 vs. 150 and 138 mg/dL [P < 0.001 and P = 0.01] and 86% vs. 70% and 78% [P < 0.001 and P = 0.03], respectively) without increased hypoglycemia. Total daily insulin use decreased with combination therapy versus Baseline and SGLT2 inhibitor (0.41 vs. 0.56 and 0.52 units/kg/day [P < 0.001 and P = 0.002]). Peak β-hydroxybutyrate levels during IWT were lower with combination therapy than with SGLT2 inhibitor (2.0 vs. 2.4 mmol/L; P = 0.048) and similar to levels reached during the Baseline testing period (2.1 mmol/L). Participants reported enhanced treatment acceptability and satisfaction with combination therapy. CONCLUSIONS: Glucagon antagonism enhances the therapeutic effects of SGLT2 inhibition in type 1 diabetes. Combination therapy improves glycemic control, reduces insulin dosing, and suggests a strategy to unlock the benefits of SGLT2 inhibitors while mitigating the risk of diabetic ketoacidosis.
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Using the average rate of increase for the study with the highest rate of increase of BHB, it would take 5.6 or 9.6 hours to reach a BHB level of 1.6 or 3.0 mmol/L, respectively, starting at a BHB of 0.0 mmol/L.
“Using the average rate of increase for the study with the highest rate of increase of BHB, it would take 5.6 or 9.6 hours to reach a BHB level of 1.6 or 3.0 mmol/L, respectively (starting at a BHB of 0.0 mmol/L).17”
From Time to Moderate and Severe Hyperglycemia and Ketonemia Following an Insulin Pump Occlusion (2024) · cites this paper as [17]
The Results section (“GRA Therapy Reduces Ketogenesis During Insulinopenia”; page unavailable) reports that the SGLT2-inhibitor period had the highest mean ketogenesis index, supporting the premise that one study period had the fastest BHB increase. It does not report the claimed 5.6- or 9.6-hour projections from a starting BHB of 0.0 mmol/L; its reported index of 73 also does not yield those times by a simple linear calculation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFor patients with T1D using an SGLT2 inhibitor, if CSII is suspended, the rate of increase in BG (but not BHB) is lower than without the SGLT2 inhibitor.
“For patients with T1D who are using a sodium-glucose cotransporter-2 (SGLT2) inhibitor, if there is a suspension of continuous subcutaneous insulin infusion (CSII), then the rate of increase in BG (but not BHB) is lower than without the SGLT2 inhibitor.13,17”
From Time to Moderate and Severe Hyperglycemia and Ketonemia Following an Insulin Pump Occlusion (2024) · cites this paper as [17]
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Time to Moderate and Severe Hyperglycemia and Ketonemia Following an Insulin Pump Occlusion
Klonoff, D. C., Ayers, A. T., Ho, C. N., Fabris, C., Villa-Tamayo, M. F., Allen, E., Cengiz, E., Ekhlaspour, L., Wong, J. C., Heineman, L., et al. (2024) · Journal of Diabetes Science and Technology · doi:10.1177/19322968241280386 · Cited by 4 · see citing works
A New Role for Glucagon: From Secondary Hormone to Key Player
De Fano, M., Malara, M., Rucco, S., Manco, M., Fanelli, C. G., Bolli, G. B., & Porcellati, F. (2025) · Nutrition, Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2025.104233 · Cited by 1 · see citing works
- Authors
- Boeder, S. C., Thomas, R. L., Le Roux, M. J., Giovannetti, E. R., Gregory, J. M., & Pettus, J. H.
- Affiliations
- University of California San Diego (US)
- 1Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA
- Vanderbilt University (US)
- Corresponding author
- Pettus, Jeremy H.
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2024-05-22
- Volume
- 48
- Issue
- 1
- Pages
- 52-60
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC11664189
- OpenAlex
- W4398197254
- Cited by
- 25
- References
- 3
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 5
- FWCI
- 8.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes Care (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- UCSD-UCLA Diabetes Research Center (P30 DK063491)
- UC San Diego Altman Clinical and Translational Research Institute (UL1TR001442)
- Diabetes Research Connection
- Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center (DK020593)
- National Institutes of Health (2T32DK007044-41)
- JDRF (5-ECR-2020-950-A-N, 5-ECR-2022-1177-A-N)
- National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (K12DK133995, K23DK123392)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- type 1 diabetes, SGLT2 inhibitors, glucagon receptor antagonists, dapagliflozin, combination therapy, glycemic control, insulin dose reduction, insulin deficiency, ketogenesis, diabetic ketoacidosis, beta-hydroxybutyrate, continuous glucose monitoring
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Adult, Benzhydryl Compounds, Blood Glucose, Diabetes Mellitus, Type 1, Double-Blind Method, Drug Therapy, Combination, Female, Glucosides, Humans, Hypoglycemic Agents, Insulin, Male, Middle Aged, Receptors, Glucagon, Cross-Over Studies
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