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SGLT2 inhibition — a novel strategy for diabetes treatment

Nature Reviews Drug Discovery volume 9, pages 551–559 (2010)Cite this article

Subjects

Key Points

  • Side effects of current type 2 diabetes mellitus (T2DM) medications, which include hypoglycaemia, weight gain, and nausea and vomiting, can hamper glycaemic control and efforts to limit the complications of diabetes. Novel therapeutic strategies are therefore needed.

  • The kidney plays a crucial role in glucose homeostasis, mediating glucose reabsorption and, to a lesser degree, gluconeogenesis. Reabsorption of glucose in the kidney is mediated by the sodium–glucose co-transporters (SGLTs), particularly by SGLT2.

  • Although glycosuria has been historically viewed as a sign of metabolic decompensation and as an adverse clinical consequence of diabetes, inhibiting SGLT2 to increase urinary glucose excretion is emerging as a promising new strategy to treat T2DM. Importantly, it does not affect insulin action or secretion, which are common targets of existing T2DM medications.

  • Phlorizin, a compound isolated from the root bark of apple trees, was used in multiple investigations that helped to establish that hyperglycaemia contributes to the insulin resistance that characterizes T2DM. It was later identified to be a nonselective SGLT inhibitor, acting on both SGLT1 and SGLT2. However, this and other early SGLT inhibitors, such as T-1095, sergliflozin and remogliflozin, were probably not further developed because of difficulties with stability, nonselective inhibition and low bioavailability.

  • More recently, in several randomized, double-blind, placebo-controlled Phase III clinical trials, the SGLT2-selective inhibitor dapagliflozin has demonstrated statistically significant reductions in glycated haemoglobin A1c (HbA1c), as well as dose-dependent decreases in weight. Multiple agents, including canagliflozin, are also undergoing clinical trials and further data are anticipated to be reported in the near future.

  • Safety concerns associated with SGLT2 inhibition include the potential development of hypoglycaemia, urinary tract infections, renal dysfunction and genitourinary fungal infections. Together with observations of normal renal function in patients with genetic mutations in the SGLT2 gene — familial renal glycosuria — who have significant glycosuria, data from studies conducted so far have, to a degree, been reassuring.

  • Although data from further investigations are forthcoming, studies so far show that SGLT2 inhibitors may have a role in not only enhancing glycaemic control, but also potentially improving obesity and leading to blood pressure reduction through diuretic effects.

Abstract

Inhibiting sodium–glucose co-transporters (SGLTs), which have a key role in the reabsorption of glucose in the kidney, has been proposed as a novel therapeutic strategy for diabetes. Genetic mutations in the kidney-specific SGLT2 isoform that result in benign renal glycosuria, as well as preclinical and clinical studies with SGLT2 inhibitors in type 2 diabetes, support the potential of this approach. These investigations indicate that elevating renal glucose excretion by suppressing SGLT2 can reduce plasma glucose levels, as well as decrease weight. Although data from ongoing Phase III trials of these agents are needed to more fully assess safety, results suggest that the beneficial effects of SGLT2 inhibition might be achieved without exerting significant side effects — an advantage over many current diabetes medications. This article discusses the role of SGLT2 in glucose homeostasis and the evidence available so far on the therapeutic potential of blocking these transporters in the treatment of diabetes.

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Figure 1: SGLT2 mediates glucose reabsorption in the kidney.
Figure 2: Normal glucose homeostasis.
Figure 3: Renal handling of glucose in a non-diabetic individual.
Figure 4: Renal glucose handling before and following inhibition of SGLT2.
Figure 5: Available structures of SGLT inhibitors.

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References

  1. Prentki, M. & Nolan, C. J. Islet cell failure in type 2 diabetes. J. Clin. Invest. 116, 1802–1812 (2006).

    Article  CAS  Google Scholar 

  2. Kaiser, N. & Leibowitz G. J. Glucotoxicity and beta-cell failure in type 2 diabetes mellitus. J. Pediatr. Endo. Metab. 16, 5–22 (2003).

    CAS  Google Scholar 

  3. Inzucchi, S. E. Oral antihyperglycemic therapy for type 2 diabetes. JAMA 287, 360–372 (2002).

    Article  CAS  Google Scholar 

  4. Buse, J. B. et al. Effects of exenatide (Exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27, 2628–2635 (2004).

    Article  CAS  Google Scholar 

  5. Farber, S. J., Berger E. Y. & Earle D. P. Effect of diabetes and insulin of the maximum capacity of the renal tubules to reabsorb glucose. J. Clin. Invest. 30, 125–129 (1951).

    Article  CAS  Google Scholar 

  6. Jabbour, S. A. & Goldstein, B. J. Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes. Int. J. Clin. Pract. 62, 1279–1284 (2008).

    Article  CAS  Google Scholar 

  7. Brown, G. K. Glucose transporters: structure, function, and consequences of deficiency. J. Inherited Metab. Dis. 23, 237–246 (2000).

    Article  CAS  Google Scholar 

  8. Wright, E. M. & Turk, E. The sodium/glucose cotransport family SLC5. Pflugers Arch. 447, 510–518 (2004).

    Article  CAS  Google Scholar 

  9. Rahmoune, H. et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 54, 3427–3434 (2005). This preclinical study is the first demonstration in a human model that elevated renal glucose transporter expression and function are associated with T2DM.

    Article  CAS  Google Scholar 

  10. Wright, E. M. Renal Na–glucose cotransporters. Am. J. Renal Physiol. 280, F10–F18 (2001).

    Article  CAS  Google Scholar 

  11. Lee, Y. J. & Han, H. J. Regulatory mechanisms of Na+/glucose cotransporters in renal proximal tubule cells. Kidney Int. Suppl. 106, S27–S35 (2007).

    Article  CAS  Google Scholar 

  12. Abdul-Ghani, M. A., DeFronzo, R. A. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr. Pract. 14, 782–790 (2008).

    Article  Google Scholar 

  13. Nathan, D. M. Long-term complications of diabetes mellitus. N. Engl. J. Med. 328, 1676–1685 (1993).

    Article  CAS  Google Scholar 

  14. Santer, R. et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J. Am. Soc. Nephrol. 14, 2873–2882 (2003).

    Article  CAS  Google Scholar 

  15. Ehrenkranz, J. R., Lewis, N. G., Kahn, C. R. & Roth, J. Phlorizin: a review. Diabetes Metab. Res. Revs. 21, 31–38 (2005).

    Article  CAS  Google Scholar 

  16. Rossetti, L., Smith, D., Shulman, G. I., Papachristou, D. & DeFronzo, R. A. Correction of hyperglycemia with phlorizin normalizes tissues sensitivity to insulin in diabetic rats. J. Clin. Invest. 79, 1510–1515 (1987). This manuscript presents the first in vivo studies that link hyperglycaemia with the development of insulin resistance.

    Article  CAS  Google Scholar 

  17. Freitas, H. S. et al. Na+–glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1α expression and activity. Endocrinology 149, 717–724 (2008).

    Article  CAS  Google Scholar 

  18. Oku, A. et al. T-1095, an inhibitor of renal Na+–glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes 48, 1794–1800 (1999).

    Article  CAS  Google Scholar 

  19. Hussey, E. K. et al. Multiple-dose pharmacokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy overweight and obese subjects: a randomized double-blind study. J. Clin. Pharmacol. 3 Mar 2010 (doi:10.1177/0091270009352185).

    Article  CAS  Google Scholar 

  20. Fujimori, Y. et al. Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models. J. Pharmacol. Exp. Ther. 327, 268–276 (2008).

    Article  CAS  Google Scholar 

  21. Meng, W. et al. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 51, 1145–1149 (2008). The authors detail the initial identification of dapagliflozin, the first agent in a new class of oral selective SGLT2 inhibitors.

    Article  CAS  Google Scholar 

  22. Han, S. et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 57, 1723–1729 (2008).

    Article  CAS  Google Scholar 

  23. Komoroski, B. et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin. Pharmacol. Ther. 85, 520–526 (2009). The first studies on this agent in humans are discussed in this paper. It describes single-ascending and multiple-ascending dose studies of dapagliflozin, and found that it produced dose-dependent glycosuria in healthy volunteers.

    Article  CAS  Google Scholar 

  24. Komoroski, B., Vachharajani, N., Feng, Y., Li, L., Kornhauser, D. & Pfister, M. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin. Pharmacol. Ther. 85, 513–519 (2009). Dapagliflozin was first shown in this clinical investigation to produce elevations in glycosuria that were dose-dependent in patients with T2DM. It also demonstrated improvements in fasting plasma glucose and postprandial glucose (post-oral-glucose-tolerance test) that were independent of effects on insulin.

    Article  CAS  Google Scholar 

  25. List, J. F., Woo, V., Morales, E., Tang, W. & Fiedorek, F. T. Sodium–glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 32, 650–657 (2009).

    Article  CAS  Google Scholar 

  26. Wilding, J. P. et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care 32, 1656–1662 (2009). The authors provide evidence that SGLT2 inhibition can reduce weight and blood glucose in patients with T2DM who, despite being on high doses of insulin and oral insulin-sensitizer therapy, are suboptimally controlled.

    Article  CAS  Google Scholar 

  27. Bailey, C. J., Gross, J. L., Bastone, L., Bastien, A. & List, J. F. Dapagliflozin as an add-on to metformin lowers hyperglycemia in type 2 diabetes patients inadequately controlled with metformin alone. Diabetologia 52, S76 (2009).

    Google Scholar 

  28. Nomura, S., Sakamaki, S. & Hongu, M. Discovery of novel C-glucosides with thiophene ring as sodium dependent glucose cotransporter 2 inhibitors for the treatment of type 2 diabetes mellitus. [Abstract MEDI 151]. American Chemical Society website [online], (2009).

    Google Scholar 

  29. Johnson & Johnson Pharmaceutical Research & Development, L.L.C. CANagliflozin Treatment And Trial Analysis-Sulfonylurea (CANTATA-SU) SGLT2 add-on to metformin versus glimepiride. ClinicalTrials.gov Idenitifier: NCT00968812. ClinicalTrials.gov website [online], (2010).

  30. Johnson & Johnson Pharmaceutical Research & Development, L.L.C. The CANTATA-M (CANagliflozin Treatment and Trial Analysis — Monotherapy) Trial. ClinicalTrials.gov Idenitifier: NCT01081834. ClinicalTrials.gov website [online], (2010).

  31. Johnson & Johnson Pharmaceutical Research & Development, L.L.C. The CANTATA-MSU Trial (Canagliflozin Treatment And Trial Analysis — Metformin and Sulphonylurea). ClinicalTrials.gov Idenitifier: NCT01106625. ClinicalTrials.gov website [online], (2010).

  32. Johnson & Johnson Pharmaceutical Research & Development, L.L.C. The CANTATA-D Trial (Canagliflozin Treatment and Trial Analysis — DPP-4 Inhibitor Comparator Trial). ClinicalTrials.gov Idenitifier: NCT01106677. ClinicalTrials.gov website [online], (2010).

  33. Grempler, G. et al. In vitro properties and in vivo effect on urinary glucose excretion of BI 10773, a novel selective SGLT2 inhibitor. [Abstract 521-P]. American Diabetes Association website [online], (2009).

    Google Scholar 

  34. Bhanot, S. et al. ISIS 388626, an SGLT2 antisense drug, causes robust and sustained glucosuria in multiple species and is safe and well-tolerated. [Abstract 328-OR]. American Diabetes Association website [online], (2009).

    Google Scholar 

  35. Wancewicz, E. V. et al. Long term safety and efficacy of ISIS 388626, an optimized SGLT2 antisense inhibitor, in multiple diabetic and euglycemic species. [Abstract 334-OR]. American Diabetes Association website [online], (2008).

    Google Scholar 

  36. Calado, J., Soto, K., Clemente, C., Correia, P. & Rueff, J. Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria. Hum. Genet. 114, 314–316 (2004).

    Article  Google Scholar 

  37. van den Heuvel, L. P., Assink, K., Willemsen, M. & Monnens, L. Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2). Hum. Genet. 111, 544–547 (2002).

    Article  CAS  Google Scholar 

  38. Bakris, G. L., Fonseca, V. A., Sharma, K. & Wright, E. M. Renal sodium–glucose transport: role in diabetes and potential clinical implications. Kidney Int. 75, 1272–1277 (2009).

    Article  CAS  Google Scholar 

  39. Wright, E. M. in Metabolic Basis of Inherited Disease (eds Scriver, C. R., Beaudet, A. L., Sly, W. S. & Valle, D.) 4891–4908 (McGraw-Hill, New York, 2001).

    Google Scholar 

  40. Zhou, L. et al. Human cardiomyocytes express high levels of Na+/glucose cotransporter1 (SGLT1). J. Cell Biochem. 90, 339–346 (2003).

    Article  CAS  Google Scholar 

  41. Wright, E. M. Genetic disorders of membrane transport: glucose galactose malabsorption. Am. J. Physiol. Gastrointest. Liver Physiol. 275, 879–892 (1998).

    Article  Google Scholar 

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Acknowledgements

This project was supported by the Veterans Administration Medical Center, San Diego and the University of California, San Diego, USA.

Author information

Authors and Affiliations

  1. Section of Endocrinology, Metabolism and Diabetes, VA San Diego Healthcare System and University of California, San Diego School of Medicine, 3350 La Jolla Village Drive, 111 G, San Diego, 92161, California, USA

    Edward C. Chao & Robert R. Henry

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  1. Edward C. Chao
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  2. Robert R. Henry
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Corresponding author

Correspondence to Edward C. Chao.

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Competing interests

Robert R. Henry has consulting agreements and serves on the advisory boards of several pharmaceutical companies that are developing SGLT2 inhibitors for therapeutic uses. These include Bristol-Myers Squibb, Astra Zeneca, Johnson and Johnson, Roche Pharmaceuticals, Boehringer Ingelheim, GlaxoSmithKline Pharmaceuticals, and Isis Pharmaceuticals.

Related links

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DATABASES

OMIM

Familial renal glycosuria

FURTHER INFORMATION

ClinicalTrials.gov

Division of Endocrinology and Metabolism, UCSD Department of Medicine

The Center for Metabolic Research, VA San Diego Healthcare System

Glossary

Sodium-glucose co-transporters

(SGLTs). A family of membrane proteins that transport glucose, as well as some ions, vitamins and amino acids across the brush-border membrane of the proximal convoluted tubules in the kidney and epithelial cells in the intestine.

Familial renal glycosuria

A genetic disorder of the renal tubules characterized by persistent isolated glycosuria without hyperglycaemia. The disorder results from mutations in SLC5A2, the gene encoding sodium–glucose co-transporter 2.

Glucose excursion

This is usually defined as the change in glucose concentration from before to after a meal. In research settings this is pre- and post-oral-glucose-tolerance tests.

Antisense oligonucleotide inhibitor

When the sequence of a particular gene is known to cause a particular disease, a strand of nucleic acid can be synthesized (DNA, RNA or a chemical analogue) that will bind to the mRNA produced by that gene and inactivate that gene. Antisense is complementary to the 'sense' sequence of the target gene's mRNA.

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Chao, E., Henry, R. SGLT2 inhibition — a novel strategy for diabetes treatment. Nat Rev Drug Discov 9, 551–559 (2010). https://doi.org/10.1038/nrd3180

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