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SGLT2 Inhibitors in Type 1 Diabetes: The Metabolic Perspective
Vala Hamidi1, Sunder Mudaliar2,3,4
1Department of Medicine, Division of Endocrinology, Diabetes and Metabolsim, University of California, San Diego, CA, USA. vhamidi@health.ucsd.edu.
Handbook of Experimental Pharmacology
|August 12, 2026
Summary
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) offer glycemic and cardiorenal benefits. This review explores their metabolic effects and risks, like diabetic ketoacidosis (DKA), in type 1 diabetes (T1DM) management.
Area of Science:
- Endocrinology
- Metabolic Diseases
- Pharmacology
Background:
- Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are established treatments for type 2 diabetes (T2DM), offering glycemic control and cardiorenal benefits.
- Current approvals include benefits for heart failure (HF) and chronic kidney disease (CKD) in T2DM and even in non-diabetic individuals.
- However, SGLT2i are contraindicated in type 1 diabetes (T1DM) due to an elevated risk of diabetic ketoacidosis (DKA).
Purpose of the Study:
- To review the metabolic effects of SGLT2 inhibitors and dual SGLT1/2 inhibitors in patients with T1DM.
- To examine the mechanisms behind increased ketogenesis and DKA risk in T1DM patients using these agents.
- To discuss potential strategies for mitigating DKA risk, enabling T1DM patients to access SGLT2i benefits.
Main Methods:
- Literature review of metabolic effects associated with SGLT2 inhibitors in T1DM.
- Analysis of mechanisms influencing glycemia, insulin sensitivity, and substrate oxidation.
- Investigation into ketogenesis pathways and DKA risk factors.
Main Results:
- SGLT2i demonstrate beneficial glycemic effects in T1DM despite increased endogenous glucose production (EGP).
- Metabolic changes include altered insulin sensitivity, hyperglucagonemia, and shifts in substrate oxidation.
- Increased ketogenesis and a higher propensity for DKA are observed in T1DM patients.
Conclusions:
- SGLT2 inhibitors present a complex metabolic profile in T1DM, with both benefits and risks.
- Understanding the mechanisms of increased DKA risk is crucial for safe T1DM management with SGLT2i.
- Mitigation strategies may allow T1DM patients to safely utilize the cardiorenal and glycemic advantages of SGLT2 inhibitors.
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