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The Potential Role of SGLT2 Inhibitors in the Treatment of Type 1 Diabetes Mellitus

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Abstract

Type 1 diabetes mellitus is a difficult disease to treat due to the relative paucity of therapeutic options other than injectable insulin. The latter, however, can induce hypoglycemia, which has been linked to enhanced cardiovascular risk. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-hyperglycemic medications that do not increase the hypoglycemia risk and are US Food and Drug Administration (FDA) approved in type 2 diabetes mellitus. SGLT2 inhibitors may also be of benefit in type 1 diabetic patients, in addition to insulin, although they have not yet been approved for this indication. By blocking SGLT2 in the early proximal tubules of the kidney, these drugs decrease renal glucose retention, which is enhanced in hyperglycemia, thereby improving blood glucose control, in type 1 and type 2 diabetic patents. Their low hypoglycemia risk is due to the compensating reabsorption capacity of another glucose transporter, SGLT1, in the downstream late proximal tubule and the body’s metabolic counter-regulation, which remains intact during SGLT2 inhibition. When insulin dosage is lowered too much, SGLT2 inhibitors can enhance ketogenesis to the extent that the risk of diabetic ketoacidosis increases, particularly in type 1 diabetic patients. SGLT2 inhibitors improve the renal and cardiovascular outcome in type 2 diabetic patients. The mechanisms likely include a reduction in glomerular hyperfiltration, blood pressure, volume overload, and body weight, as well as lowering blood glucose without increasing the hypoglycemia risk. The same mechanistic effects are induced in type 1 diabetic patients. More studies are needed with SGLT2 inhibitors in type 1 diabetic patients, including renal and cardiovascular clinical outcome trials, to fully evaluate their therapeutic potential in this specific population.

Notes

Acknowledgements

The authors were supported by NIH Grants R01DK112042, R01DK106102, the UAB/UCSD O’Brien Center of Acute Kidney Injury NIH-P30DK079337, the NIH training Grant T32DK104717-02, and the Department of Veterans Affairs.

Compliance with Ethical Standards

Conflict of interest

Over the past 36 months, V.V. has served as a consultant and received honoraria from Bayer, Boehringer Ingelheim, Intarcia Therapeutics, Astra-Zeneca, Janssen Pharmaceutical, Eli Lilly and Merck, and received grant support for investigator-initiated research from Astra-Zeneca, Bayer, Boehringer Ingelheim, Fresenius, and Janssen. H.F. has no conflicting interests to disclose.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Nephrology-Hypertension, Department of MedicineUniversity of California, San DiegoSan DiegoUSA
  2. 2.VA San Diego Healthcare SystemSan DiegoUSA
  3. 3.Department of PharmacologyUniversity of California, San DiegoSan DiegoUSA

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