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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.

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References

  1. Heerspink HJL, Perkins BA, Fitchett DH, et al. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus. Circulation. 2016;134:752–72.

    Article  PubMed  CAS  Google Scholar 

  2. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017;60:215–25.

    Article  PubMed  CAS  Google Scholar 

  3. Norton L, Shannon CE, Fourcaudot M, et al. Sodium-glucose co-transporter (SGLT) and glucose transporter (GLUT) expression in the kidney of type 2 diabetic subjects. Diabetes Obes Metab. 2017;19:1322–6.

    Article  PubMed  CAS  Google Scholar 

  4. Solini A, Rossi C, Mazzanti CM, et al. Sodium-glucose co-transporter (SGLT)2 and SGLT1 renal expression in patients with type 2 diabetes. Diabetes Obes Metab. 2017;19:1289–94.

    Article  PubMed  CAS  Google Scholar 

  5. Wang XX, Levi J, Luo Y, et al. SGLT2 Protein Expression Is Increased in Human Diabetic Nephropathy: SGLT2 PROTEIN INHIBITION DECREASES RENAL LIPID ACCUMULATION, INFLAMMATION, AND THE DEVELOPMENT OF NEPHROPATHY IN DIABETIC MICE. J Biol Chem. 2017;292:5335–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Song P, Onishi A, Koepsell H, Vallon V. Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus. Exp Opin Ther Targets. 2016;20:1109–25.

    Article  CAS  Google Scholar 

  7. Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75:33–59.

    Article  PubMed  CAS  Google Scholar 

  8. Vallon V, Thomson SC. Diabetes mellitus: cardiovascular and renal benefits of SGLT2 inhibition: insights from CANVAS. Nat Rev Nephrol. 2017;13:517–8.

    Article  PubMed  CAS  Google Scholar 

  9. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.

    Article  PubMed  CAS  Google Scholar 

  10. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.

    Article  PubMed  CAS  Google Scholar 

  11. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.

    Article  PubMed  CAS  Google Scholar 

  12. American Diabetes Association AD. 6. Glycemic targets: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41:S55–64.

    Article  Google Scholar 

  13. Khunti K, Davies M, Majeed A, et al. Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study. Diabetes Care. 2015;38:316–22.

    Article  PubMed  Google Scholar 

  14. American Diabetes Association AD. 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41:S73–85.

    Article  Google Scholar 

  15. De Ferranti SD, De Boer IH, Fonseca V, et al. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Diabetes Care. 2014;37:2843–63.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Henry RR, Thakkar P, Tong C, et al. Efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diabetes Care. 2015;38:2258–65.

    Article  PubMed  CAS  Google Scholar 

  17. Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5:864–76.

    Article  PubMed  CAS  Google Scholar 

  18. Garg SK, Henry RR, Banks P, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med. 2017. https://doi.org/10.1056/nejmoa1708337.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Sands AT, Zambrowicz BP, Rosenstock J, et al. Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetes. Diabetes Care. 2015;38:1181–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14:83–90.

    Article  PubMed  CAS  Google Scholar 

  21. Ogawa W, Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. J Diabetes Investig. 2016;7:135–8.

    Article  PubMed  CAS  Google Scholar 

  22. Qiu H, Novikov A, Vallon V. Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: basic mechanisms and therapeutic perspectives. Diabetes Metab Res Rev. 2017;33:e2886.

    Article  Google Scholar 

  23. Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium–glucose cotransporter 2 inhibition. Diabetes Care. 2015;38:1687–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. US Food and Drug Administration. FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. FDA Drug Saf Commun. 2015;2–4.

  25. Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System. Diabetologia. 2017;60:1385–9.

    Article  PubMed  CAS  Google Scholar 

  26. Blau JE, Tella SH, Taylor SI, Rother KI. Ketoacidosis associated with SGLT2 inhibitor treatment: analysis of FAERS data. Diabetes Metab Res Rev. 2017;33:e2924.

    Article  CAS  Google Scholar 

  27. Jerums G, Premaratne E, Panagiotopoulos S, MacIsaac RJ. The clinical significance of hyperfiltration in diabetes. Diabetologia. 2010;53:2093–104.

    Article  PubMed  CAS  Google Scholar 

  28. Magee GM, Bilous RW, Cardwell CR, et al. Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia. 2009;52:691–7.

    Article  PubMed  CAS  Google Scholar 

  29. Vallon V, Blantz RC, Thomson, S. Glomerular hyperfiltration and the salt paradox in early type 1 diabetes mellitus: a tubulo-centric view. J Am Soc Nephrol. 2003;14:530–7.

    Article  PubMed  Google Scholar 

  30. Vallon V, Richter K, Blantz RC, et al. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol. 1999;10:2569–76.

    PubMed  CAS  Google Scholar 

  31. Thomson SC, Rieg T, Miracle C, et al. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. AJP Regul Integr Comp Physiol. 2012;302:R75–83.

    Article  CAS  Google Scholar 

  32. Vallon V, Rose M, Gerasimova M, et al. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. AJP Ren Physiol. 2013;304:F156–67.

    Article  CAS  Google Scholar 

  33. Vallon V, Thomson SC. Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu Rev Physiol. 2012;74:351–75.

    Article  PubMed  CAS  Google Scholar 

  34. Vallon V, Gerasimova M, Rose MA, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. AJP Ren Physiol. 2014;306:F194–204.

    Article  CAS  Google Scholar 

  35. Cherney DZI, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587–97.

    Article  PubMed  CAS  Google Scholar 

  36. Scheen AJ, Delanaye P. Effects of reducing blood pressure on renal outcomes in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME. Diabetes Metab. 2017;43:99–109.

    Article  PubMed  CAS  Google Scholar 

  37. Scheen AJ. Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME. Diabetes Res Clin Pract. 2016;121:204–14.

    Article  PubMed  CAS  Google Scholar 

  38. Bolinder J, Ljunggren O, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97:1020–31.

    Article  PubMed  CAS  Google Scholar 

  39. Yokono M, Takasu T, Hayashizaki Y, et al. SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. Eur J Pharmacol. 2014;727:66–74.

    Article  PubMed  CAS  Google Scholar 

  40. Pessoa TD, Campos LCG, Carraro-Lacroix L, et al. Functional role of glucose metabolism, osmotic stress, and sodium-glucose cotransporter isoform-mediated transport on Na+/H+ exchanger isoform 3 activity in the renal proximal tubule. J Am Soc Nephrol. 2014;25:2028–39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Layton AT, Vallon V. SGLT2 inhibition in a kidney with reduced nephron number: modeling and analysis of solute transport and metabolism. Am J Physiol Renal Physiol. 2018. https://doi.org/10.1152/ajprenal.00551.2017 (Epub ahead of print).

    Article  PubMed  Google Scholar 

  42. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a thrifty substrate hypothesis. Diabetes Care. 2016;39:1108–14.

    Article  PubMed  Google Scholar 

  43. Pharmacodynamics, pharmacokinetics, and safety of ASP1941 in patients with type 1 diabetes mellitus—Full Text View—ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02529449?cond = SGLT2 + type + 1+diabetes&rank = 2. Accessed 28 Jul 2017.

  44. A study of ASP1941 in combination with insulin in patients with type 1 diabetes mellitus—Full Text View—ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02897219?cond = SGLT2 + type + 1+diabetes&rank = 1. Accessed 28 Jul 2017.

  45. Effects of single doses of liraglutide and dapagliflozin on hyperglycemia and ketogenesis in type 1 diabetes—Full Text View—ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02777073?cond = SGLT2 + type + 1+diabetes&rank = 3. Accessed 28 Jul 2017.

  46. Empagliflozin as adjunctive to insulin therapy over 26 weeks in patients with T1DM (EASE-3)—Full Text View—ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02580591?term = empagliflozin&cond = type + 1+diabetes&rank = 6. Accessed 20 Mar 2018.

  47. Empagliflozin as Adjunctive to InSulin thErapy over 52 weeks in patients with type 1 diabetes mellitus (EASE-2)—Full Text View—ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02414958?term = empagliflozin&cond = type + 1+diabetes&rank = 3. Accessed 20 Mar 2018.

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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.

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Correspondence to Hadi Fattah or Volker Vallon.

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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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Fattah, H., Vallon, V. The Potential Role of SGLT2 Inhibitors in the Treatment of Type 1 Diabetes Mellitus. Drugs 78, 717–726 (2018). https://doi.org/10.1007/s40265-018-0901-y

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