SGLT2 inhibitors as adjunctive therapy for type 1 diabetes: Balancing benefits and risks
Open accessAbstract
Sodium-glucose co-transporter-2 (SGLT2) inhibitors have several beneficial effects in patients with type 2 diabetes, including glucose lowering, weight loss, blood pressure lowering, and a reduced risk of major adverse cardiovascular events. To address high unmet medical need via improved glycaemic control, several clinical trials have been done to assess the efficacy and safety of SGLT2 inhibitors in combination with insulin therapy in patients with type 1 diabetes. In this Personal View, we summarise data from eight clinical trials of canagliflozin, dapagliflozin, empagliflozin, and sotagliflozin in patients with type 1 diabetes. HbA 1c-lowering efficacy was greatest at 8-12 weeks of therapy, but the magnitude of HbA 1c lowering waned with longer duration of treatment (up to 52 weeks). Data are not yet available to establish for how long glycaemic efficacy could be sustained during long-term therapy in patients with type 1 diabetes. Moreover, SGLT2 inhibitor therapy induces serious adverse events, including a roughly six-times increased risk of diabetic ketoacidosis. The US Food and Drug Administration estimated that one additional case of ketoacidosis will occur for every 26 patient-years of exposure of patients with type 1 diabetes to sotagliflozin therapy. Assuming a case mortality of 0·4%, this estimate translates into 16 additional deaths per year per 100 000 patients with type 1 diabetes undergoing treatment. These considerations raise important questions about the risk-to-benefit profile of SGLT2 inhibitors when used as adjunctive therapy in patients with type 1 diabetes.
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Pramlintide is the only other medication approved for type 1 diabetes and is given with prandial insulin.
“The amylin analog pramlintide, the only other medication approved for the treatment of T1D, is administered with prandial insulin.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1174]
The Introduction (page unavailable) says adjunctive therapies have been added to insulin for type 1 diabetes, and reference 5 identifies pramlintide as one such therapy. Our copy does not say that pramlintide is the only other approved medication or that it is administered specifically with prandial insulin. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAn increased rate of DKA led to rejection of market authorization for type 1 diabetes by the FDA, whereas the EMA has approved low-dose dapagliflozin (5 mg) and sotagliflozin (200 mg) for those with BMI ≥27 kg/m2.
“However, an increased rate of DKA led to rejection of market authorization for type 1 diabetes by the FDA, whereas the European Medicines Agency has approved low-dose dapagliflozin (5 mg) and sotagliflozin (200 mg) for those with a BMI $27 kg/m 2 (261).”
From The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2021) · cites this paper as [261]
The Introduction reports a positive EMA committee opinion for dapagliflozin in patients with type 1 diabetes and BMI ≥27 kg/m², and the Clinical Outcomes section documents increased ketoacidosis risk. But the paper does not report an FDA rejection caused by that risk or EMA approval of both drugs at the stated doses; it says sotagliflozin was still under FDA review and describes the doses as approved or proposed. (LLM, conf=0.90)
Experimental — accuracy not yet measuredNausea is a common adverse effect of pramlintide.
“Nausea is a common adverse effect.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1174]
The References section lists a study of pramlintide but says nothing about its adverse effects. Searches for “nausea” and “pramlintide adverse effect nausea” found no passage in our copy stating that nausea is a common adverse effect of pramlintide. (LLM, conf=0.75)
Experimental — accuracy not yet measuredPramlintide carries a potential risk of severe hypoglycemia if the prandial insulin dose is not appropriately reduced.
“There is a potential risk of severe hypoglycemia if persons with DM do not appropriately reduce the prandial insulin dosage.1171–1174”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1174]
The Clinical Trial Design and Clinical Outcomes sections discuss reducing insulin doses to mitigate hypoglycemia risk when starting SGLT2 inhibitors, not pramlintide. A search for pramlintide found it only in a References entry; our copy does not address whether failing to reduce prandial insulin with pramlintide raises the risk of severe hypoglycemia. Page numbers were unavailable. (LLM, conf=0.76)
Experimental — accuracy not yet measuredPramlintide produces consistently modest A1C reductions, and mild weight loss is common.
“A1C reductions are consistently modest, and mild weight loss is common.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1174]
The Clinical Outcomes: Glycemic Efficacy and Other Secondary Outcomes sections report modest HbA1c reductions and weight loss for SGLT2 inhibitors, not pramlintide. A search for pramlintide found it in a reference title, but no passage in our copy reports its effects on A1C or weight. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Tachyphylaxis often occurs after several years of pramlintide therapy.
“Tachyphylaxis is often seen after several years of therapy.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1174]
Our copy mentions pramlintide in a reference to a long-term efficacy study, but does not report tachyphylaxis during pramlintide therapy. The waning efficacy described in Clinical Outcomes: Glycemic Efficacy concerns SGLT2 inhibitors over weeks, not pramlintide after several years. Searches for pramlintide, tachyphylaxis, and long-term waning found no passage supporting the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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- Authors
- Taylor, S. I., Blau, J. E., Rother, K. I., & Beitelshees, A. L.
- Affiliations
- University of Maryland, Baltimore (US)
- National Institutes of Health (US)
- Corresponding author
- Taylor, Simeon I
- Venue
- The Lancet Diabetes & Endocrinology
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 7
- Issue
- 12
- Pages
- 949-958
- ISSN
- 2213-8587 (ISSN-L)
- PMC
- PMC6872914
- OpenAlex
- W2979151493
- Cited by
- 124
- References
- 35
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 18 · 2023: 23 · 2022: 15 · 2021: 19 · 2020: 15 · 2019: 1
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Diabetes & Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK118942)
- 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
- SGLT2 inhibitors, type 1 diabetes, adjunctive therapy, insulin therapy, canagliflozin, dapagliflozin, empagliflozin, sotagliflozin, diabetic ketoacidosis, risk-benefit profile, glycemic control, adverse events
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Blood Glucose, Clinical Trials as Topic, Diabetes Mellitus, Type 1, Humans, Hypoglycemic Agents
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